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[(recognition)-596.5(by)-595.4(neutralizing)-604.7(antibodies)-595.3(\(NAbs\))-601.3(has)-591.8(been)]TJ T* [(proposed)-510.8(to)-503.4(reduce)-511.2(these)-514.6(immune)-505.7(responses.)-510.4(Taking)-510.2(ad-)]TJ 0 -1.1174 TD [(vantage)-276.3(of)-278.6(the)-275.3(diversity)-276.2(of)-272.9(AdV)-275.8(capsid)-279.6(protein)-274(isoforms)-274.7(and)]TJ 0 -1.1116 TD [(their)-404.3(variety)-401.9(of)-399.6(ligandreceptor)-407.4(interactions,)-406.3(vectors)-401.6(based)]TJ T* [(on)-503.3(low)-499.6(seroprevalent)-508.6(AdVs)-501.3(could)-502.1(potentially)-504.7(enable)-505.6(tar-)]TJ 0 -1.1174 TD [(geting)-463(to)-463.1(different)-467.4(cell)-467.8(types)-461.6(as)-463.9(well)-467.5(as)-463.9(overcoming)-463.9(pre-)]TJ 0 -1.1116 TD [(existing)-545.8(immunity.)-539.2(Naturally,)-546.8(nonhuman)-541.1(AdV)-546.5(\(NHAdV\))]TJ T* [(species)-298.9(have)-289(a)-296(low)-292.3(seroprevalence)-298.7(in)-290.3(all)-292.7(human)-290.1(populations)]TJ T* [(and)-465.2(therefore)-468.4(represent)-468.3(a)-468.8(source)-463.7(of)-468.7(potential)-467.8(vectors)-465(that)]TJ 0 -1.1174 TD [(could)-410(t)-411.1(this)-413.4(niche.)-414.6(Since)-411(the)-413.5(beginning)-414.5(of)-411.1(their)-410.1(develop-)]TJ 0 -1.1116 TD [(ment)-410.1(in)-405.5(1990s)-402.7(\()-87.5(Mittal)]TJ /F7 1 Tf 9.6763 0 TD [(et)-406.7(al.)]TJ /F4 1 Tf 2.1657 0 TD [(,)-406.6(1995\),)-406.3(recombinant)-414.5(NHAdV)]TJ -11.842 -1.1116 TD [(vectors)-424.6(have)-421.4(been)-421.4(derived)-419.1(from)-420.3(many)-421.5(different)-421.3(AdV)-419.7(spe-)]TJ 0 -1.1174 TD [(cies:)-474.4(canin)-8(e)-468.8(AdV-2)-479.5(\(CAdV-2\),)-475.7(bovine)-474.4(AdV-3)-479.5(\(BAdV-3\),)]TJ 0 -1.1116 TD [(porcine)-338.4(AdV-3)-341.3(\(PAdV-3\),)-336.3(ovine)-340.9(AdV-7)-335.5(\(OAdV-7\),)-343.1(murine)]TJ T* [(AdV-1)-715.7(\()-81.7(MAdV-1\),)-716.4(several)-713.8(simian)-711.7(\(SAdVs\),)-715.2(and)-712.9(fowl)]TJ 0 -1.1174 TD [(\(FAdVs\))-274(AdVs.)-268.6(Here)-272.5(we)-274.9(outline)-268.4(the)-269.5(current)-275(status)-272.6(of)-267.1(HAdV)]TJ 0 -1.1116 TD [(vectors,)-497.2(summarize)-499.6(the)-494.2(development)-500.9(of)-491.7(NHAdV)-498.6(vectors,)]TJ T* [(and)-332.8(discuss)-336.7(the)-332.9(advantages)-338.2(and)-338.5(shortfalls)-334.7(of)-336.2(each.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 193.6062 Tm [(Innate)-335.6(and)-331.9(Adaptive)-336.5(Immune)-335.8(Responses)-332.7(Against)-338.4(AdVs)]TJ /F4 1 Tf 9.843 0 0 9.843 72 177.222 Tm [(Innate)-274(and)-275.2(adaptive)-277.5(immune)-281.1(responses)-276.6(play)-276.4(a)-273(critical)-277.7(role)]TJ -1.0137 -1.1174 TD [(in)-353.7(resolving)-356.7(AdV)-350.6(infections.)-356.8(The)-357(presence)-358.8(of)-347.7(specic)-356.6(anti-)]TJ 0 -1.1116 TD [(viral)-571.3(antibodies)-566.5(signicantly)-568.6(increases)-573(antibody)-568.9(constant)]TJ T* [(fraction)-529.7(recep)-9(tor)-527.5(\(FcR\)-dependent)-534.7(viral)-531(internalization)-534.5(in)]TJ 0 -1.1174 TD [(macrophages,)-643.3(triggering)-634.6(an)-636.9(innate)-637(immune)-638.2(response)-638.5(to)]TJ 0 -1.1116 TD [(AdVs)-397.6(that)-391.7(leads)-393.7(to)-394(type)-391.6(I)-392.7(interferon)-393.6(\(IFN\))-397.8(production)-392.6(and)]TJ T* [(caspase-dependent)-660.2(interleukin)-660(\(IL\)-1)]TJ /F8 1 Tf 15.6318 0 TD (b)Tj /F4 1 Tf 1.2038 0 TD [(maturation)-660(\(Zaiss)]TJ /F7 1 Tf -16.8356 -1.1174 TD [(et)-320.3(al.)]TJ /F4 1 Tf 2.0793 0 TD [(,)-320.2(2009\).)-319.9(Internalized)-323.5(AdV)-321.8(DNA)-316.9(induces)-326.8(maturation)-320.2(of)]TJ -2.0793 -1.1116 TD (pro-IL-1)Tj /F8 1 Tf 3.4501 0 TD (b)Tj /F4 1 Tf .887 0 TD [(in)-336.4(macrophages)-340.3(dependent)-341.8(on)-336.3(NALP3)-336.6(and)-338.5(ASC,)]TJ -4.3371 -1.1116 TD [(components)-642.3(of)-635.7(the)-638.2(innate)-637(cytosolic)-640.2(molecular)-642.7(complex)]TJ 0 -1.1174 TD [(called)-407.8(the)-407.8(inammasome,)-414.2(but)-406.6(independent)-407.5(of)-405.3(Toll-like)-410.2(re-)]TJ 0 -1.1116 TD [(ceptors)-372.8(\(TLRs\))-372.6(and)-367.3(IFN)-366.8(regulatory)-376.4(factors)-367(\()-87.5(Muruve)]TJ /F7 1 Tf 21.9157 0 TD [(et)-366.4(al.)]TJ /F4 1 Tf 2.1253 0 TD (,)Tj 1.463 67.9184 TD [(2008\).)-319.9(Later)-320.1(studies)-319.8(reported)-322.2(that)-316.9(this)-321.3(response)-321.7(requires)-322(the)]TJ 0 -1.1174 TD [(binding)-249.9(of)-244.1(the)-246.5(arginine-glycine-aspartic)-255(acid)-248.8(\(RGD\))-250.1(motif)-243.1(in)]TJ 0 -1.1116 TD [(the)-505.7(AdV)-506.1(penton)-509(base)-501.9(with)-506.6(macrophage)]TJ /F8 1 Tf 17.3886 0 TD (b)Tj /F4 1 Tf .5529 0 TD [(3)-502.2(integrins)-506.6(\(Di)]TJ -17.9415 -1.1116 TD (Paolo)Tj /F7 1 Tf 2.54 0 TD [(et)-251.2(al.)]TJ /F4 1 Tf 2.0101 0 TD [(,)-256.9(2009\).)-250.8(Barlan)-257.7(and)-257.9(colleagues)-257.6(also)-253.2(demonstrated)]TJ -4.5502 -1.1116 TD [(that)-391.7(the)-390.5(specic)-396.9(AdV)-390.9(penetration)-390.3(mechanism)-395.9(of)-388.1(the)-390.5(endo-)]TJ 0 -1.1174 TD [(somal)-572.3(membranes)-568.6(is)-566.6(required)-564.1(for)-567.7(IL-1)]TJ /F8 1 Tf 16.8068 0 TD (b)Tj /F4 1 Tf 1.1174 0 TD [(release)-571(\(Barlan)]TJ /F7 1 Tf -17.9242 -1.1116 TD [(et)-487.3(al.)]TJ /F4 1 Tf 2.2463 0 TD [(,)-481.5(2011a,b\).)-482.2(Macrophages)-489.8(and)-482.5(conventional)-489.4(dendritic)]TJ -2.2463 -1.1116 TD [(cells)-457.2(\(cDCs\))-458.7(can)-454.9(detect)-459.6(cytosolic)-455.9(AdV)-454.3(DNA)-455.2(in)-457.3(a)-451.5(TLR9-)]TJ 0 -1.1174 TD [(independen)-8.9(t)-352.6(manner)-350(\(Basner-Tschakarjan)]TJ /F7 1 Tf 17.331 0 TD [(et)-354.8(al.)]TJ /F4 1 Tf 2.1138 0 TD [(,)-349(2006;)-357(Zhu)]TJ /F7 1 Tf -19.4448 -1.1116 TD [(et)-400.9(al.)]TJ /F4 1 Tf 2.1599 0 TD [(,)-395.1(2007\),)-394.8(while)-399.5(plasmacytoid)-398.3(DCs)-396.7(\(pDCs\))-399.9(detect)-402(non-)]TJ -2.1599 -1.1116 TD [(methylated)-476.9(AdV)-465.8(CpG-c)-8.5(ontaining)-466.5(DNA)-472.5(in)-468.9(the)-471.1(endosomes)]TJ 0 -1.1174 TD [(throug)-6.7(h)-531(TLR9.)-541.2(Also,)-538.5(internalized)-542.5(HAdV-5)-539.1(and)-534.4(HAdV-6)]TJ 0 -1.1116 TD [(im)13.7(m)15(u)0(n)15.1(e)-342.1(co)19.7(mp)19.6(le)19.5(xe)13.9(s)-340.7(h)0(a)19.7(v)0(e)-337.4(b)0(e)19.7(e)0(n)-337.4(r)0(e)19.7(p)0(o)20.8(r)0(t)20.7(e)0(d)-337.4(t)0(o)-330.6(i)0(n)15(d)0(u)20.8(c)0(e)-332.8(D)0(C)-338.2(m)0(a)18.4(t)0(u)20.7(-)]TJ T* [(ra)14(ti)20.6(on)-319(vi)20.7(a)-330.6(T)0(L)18.4(R)0(9)-320(a)0(g)13.9(o)0(n)20.8(i)0(s)20.9(t)-329.5(mo)19.6(ti)20.6(fs)-324.5(pr)20.9(es)19.9(en)19.7(t)-335.3(i)0(n)-319.1(t)0(h)20.7(e)-330.6(Ad)20(V)-330.3(g)0(e)19.7(n)0(o)15.1(m)0(e)18.5(,)]TJ T* [(wh)14.2(er)19.7(ea)18.5(s)-398.3(H)0(A)13.3(d)0(V)20(-)0(3)20.9(5)0(,)-390.4(-)0(3)20.9(6)0(,)-390.4(a)0(n)19.7(d)-404.3(-2)20.9(6)-398.5(h)0(a)13.9(v)0(e)-389.3(a)-399.7(li)14.8(mi)19.5(te)19.6(d)-398.5(p)0(o)20.8(t)0(e)13.8(n)0(c)19.7(y)-398.5(to)]TJ 0 -1.1174 TD [(in)15(du)20.8(ce)-373.1(DC)-372.7(ma)18.4(tu)20.7(ra)19.7(ti)20.6(on)-370.8(be)19.7(ca)18.5(us)15.3(e)-376.6(o)0(f)-370.8(h)0(a)13.9(v)0(i)20.7(n)0(g)-370.8(a)-382.4(sm)19.8(al)19.5(le)19.5(r)-381.2(n)0(u)20.8(m)0(b)19.6(e)0(r)]TJ 0 -1.1116 TD [(of)-347.7(m)15(o)0(t)14.9(i)0(f)20.7(s)-352.2(\(P)21(er)19.7(re)14(au)]TJ /F7 1 Tf 7.7238 0 TD [(et)-343.3(al)20.7(.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-354.8(2)0(0)20.8(1)0(2)20.8(\))0(.)-344.3(T)0(L)18.5(R)0(9)-343.1(s)0(i)20.9(g)0(n)20.8(a)0(l)19.5(i)0(n)15(g)-352.4(pa)19.7(th)20.7(wa)18.8(y)-352.4(i)0(s)]TJ -9.7915 -1.1116 TD [(de)13.9(pe)19.7(nd)20.8(en)19.7(t)-479.3(o)0(n)-468.7(m)0(y)19.6(e)0(l)19.5(o)0(i)14.9(d)-473.4(di)14.9(ff)20.9(er)19.7(en)19.7(ti)14.8(at)19.5(io)20.7(n)-479.2(p)0(r)20.9(i)0(m)19.5(a)0(r)19.7(y)-479.2(re)19.7(sp)15.3(on)20.8(se)-469.7(88)]TJ 0 -1.1174 TD -.0196 Tc [(\()-95.5(M)-19.6(yD)-19.6(88)-19.6(\))-471(\()-19.6(Ya)-19.6(ma)-19.6(gu)-19.6(ch)-19.6(i)]TJ /F7 1 Tf 9.5842 0 TD 0 Tc [(et)-447(al)14.9(.)]TJ /F4 1 Tf 2.1772 0 TD [(,)-458.4(2)0(0)15.1(0)0(7)20.8(;)-456.2(Zh)19.6(u)]TJ /F7 1 Tf 5.466 0 TD [(et)-447(al)20.7(.)]TJ /F4 1 Tf 2.1772 0 TD [(,)-458.4(2)0(0)20.8(0)0(7)15.1(\))-456.1(an)19.7(d)]TJ -19.4044 -1.1116 TD [(in)15(du)20.8(ce)18.5(s)-381(t)0(h)14.9(e)-382.4(se)19.9(cr)19.7(et)19.6(io)15(n)-381.2(o)0(f)-376.5(I)0(L)19.7(-)0(6)-370.8(a)0(n)19.7(d)-387(IL)19.7(-1)20.9(2)-381.2(\()0(Y)14.2(a)0(m)18.5(a)0(g)19.7(u)0(c)19.7(h)0(i)]TJ /F7 1 Tf 21.9387 0 TD [(et)-377.9(al)20.7(.)]TJ /F4 1 Tf 2.108 0 TD (,)Tj -24.0468 -1.1116 TD [(20)15.1(07)20.8(\).)-344.3(He)18.8(pa)13.9(ri)20.7(n-)20.9(se)19.9(ns)15.3(it)20.6(iv)20.7(e)-359.4(r)0(e)19.7(c)0(e)18.5(p)0(t)20.7(o)0(r)20.9(s)-358(on)-347.8(DC)18.9(s)-358(b)0(i)20.7(n)0(d)-347.8(t)0(o)-347.9(t)0(h)20.7(e)-359.4(Ad)20(V)]TJ 0 -1.1174 TD [(sh)15.3(af)19.7(t)-225.9()0(b)21(e)0(r)-216.4(r)0(e)19.7(g)0(i)14.9(o)0(n)-215.3(a)0(n)19.7(d)-225.7(tr)20.7(ig)20.7(ge)13.9(r)-225.7(T)-221.2(ce)12.8(ll)-215.6(im)19.5(mu)19.6(ne)-216.5(re)19.7(sp)21(on)20.8(se)14.1(s)-225.5(\()0(C)19.8(h)0(e)19.7(n)0(g)]TJ /F7 1 Tf 0 -1.1116 TD [(et)-349.1(al)20.7(.)]TJ /F4 1 Tf 2.0793 0 TD [(,)-354.8(2)0(0)15.1(0)0(7)20.8(\))0(.)-344.3(H)0(A)19.1(d)0(V)14.2(-)0(5)20.9(-)0(i)20.7(n)0(d)20.8(u)0(c)19.7(e)0(d)-348.9(n)0(a)19.7(t)0(u)15(r)0(a)19.7(l)-352.6(ki)14.9(ll)20.6(er)-348.9(\(N)20(K\))-348.6(ce)18.5(ll)-348(ac)18.5(ti)20.6(-)]TJ -2.0793 -1.1116 TD [(va)13.9(ti)20.6(on)-232.6(re)19.7(li)20.6(es)-233.6(on)-232.6(T)-244.2(c)0(e)18.5(l)0(l)-232.8(c)0(o)19.7(n)0(t)20.7(r)0(i)15(b)0(u)20.8(t)0(i)20.6(o)0(n)]TJ /F7 1 Tf 13.8751 0 TD [(in)-232.7(vi)19.6(tr)15.1(o)]TJ /F4 1 Tf 3.1102 0 TD [(\(P)15.3(ah)19.7(l)]TJ /F7 1 Tf 2.3212 0 TD [(et)-233.9(al)20.7(.,)]TJ /F4 1 Tf 2.4536 0 TD [(20)20.8(12)20.8(\),)]TJ -21.7602 -1.1174 TD [(an)13.9(d)-335.2(a)0(l)19.5(s)0(o)-324.5(a)0(p)19.7(p)0(e)19.7(a)0(r)19.7(s)-340.7(to)-324.9(be)-325.9(re)19.7(la)19.6(te)19.5(d)-335.2(t)0(o)-330.6(t)0(h)20.7(e)-336.3(pr)20.9(es)19.9(en)19.7(ce)-327.1(of)-330.5(ty)20.7(pe)-325.9(I)-335.1(I)0(F)21(N)]TJ /F7 1 Tf 0 -1.1116 TD [(in)-365.2(vi)19.5(vo)]TJ /F4 1 Tf 3.1621 0 TD [(\(Z)13.9(hu)]TJ /F7 1 Tf 2.2924 0 TD [(et)-360.6(al)20.7(.)]TJ /F4 1 Tf 2.0908 0 TD [(,)-372.1(2)0(0)20.8(0)0(7)20.8(,)-372(20)15.1(08)20.8(\).)-361.6(In)-359.3(co)19.7(nt)14.9(ra)19.7(st)-359.2(to)-365.2(HA)19.1(dV)20(-5)20.9(,)-372.1(i)0(n)]TJ -7.5452 -1.1116 TD [(re)14(sp)21(on)20.8(se)-314.2(to)-319.1(HA)19.1(dV)20(-3)20.9(5)-323.6(p)0(D)20(C)0(s)-319.8(a)0(l)19.5(o)0(n)20.8(e)-324.8(ar)19.7(e)-324.8(s)0(u)15.3(f)0()21(c)0(i)19.5(e)0(n)19.7(t)-323.8(fo)15.1(r)-323.6(N)0(K)-315(c)0(e)18.5(l)0(l)]TJ T* [(ac)12.8(ti)20.6(va)19.7(ti)20.6(on)-221.1(in)-215.4(a)-226.9(T)0(L)18.4(R)0(9)19.8(-)0(d)15.1(e)0(p)19.7(e)0(n)19.7(d)0(e)19.7(n)0(t)-221.2(m)0(a)18.4(n)0(n)20.8(e)0(r)19.7(,)-228.1(af)19.7(te)19.6(r)-231.4(w)0(h)20(i)0(c)19.6(h)-225.7(NK)-222.8(ce)18.5(ll)20.6(s)]TJ 0 -1.1174 TD [(en)13.9(ha)19.7(nc)19.7(e)-342.1(p)0(D)20(C)-341.9(IF)21(N-)]TJ /F8 1 Tf 7.6777 0 TD (a)Tj /F4 1 Tf .8409 0 TD [(se)19.9(cr)14(et)19.5(io)20.7(n)-340.9(\()0(P)21(a)0(h)19.7(l)]TJ /F7 1 Tf 6.3011 0 TD [(et)-331.8(al)20.7(.)]TJ /F4 1 Tf 2.062 0 TD -.0208 Tc [(,)-364.1(2)-20.8(01)-20.8(2\))-20.8(.)-353.6(T)-5.8(h)-20.8(i)-5.9(s)-361.5(i)-20.8(nd)-20.8(i-)]TJ -16.8817 -1.1116 TD 0 Tc [(ca)12.8(te)19.5(s)-358(t)0(h)20.7(a)0(t)-354.8(b)0(o)20.8(t)0(h)-347.9(p)0(D)14.2(C)0(s)-348.6(a)0(n)19.7(d)-364(T)-359.4(c)0(e)18.5(l)0(l)20.6(s)-363.8(m)15(a)0(y)-354.7(b)0(e)-348.9(n)0(e)19.7(c)0(e)12.8(s)0(s)21.2(a)0(r)19.7(y)-358.2(fo)15.1(r)-358.2(N)0(K)]TJ T* [(ce)12.8(ll)20.6(s)-307.2(ac)18.5(ti)14.8(va)19.7(ti)20.6(on)20.8(.)-320.2(T)0(h)19.6(e)0(r)19.7(e)0(f)19.7(o)0(r)15.1(e)0(,)-311(i)0(t)-307.7(i)0(s)-307.4(c)0(l)13.8(e)0(a)18.5(r)-317.8(th)20.7(at)-308.8(di)14.9(ff)20.9(er)19.7(en)19.7(t)-318(A)0(d)14.2(V)-318.7(se)19.9(-)]TJ 0 -1.1174 TD [(ro)15.1(ty)20.7(pe)19.7(s)-254.3(c)0(a)18.5(n)-254.5(tr)15(ig)20.7(ge)19.7(r)-254.5(i)0(m)19.5(m)0(u)19.6(n)0(e)-245.3(r)0(e)14(s)0(p)21(o)0(n)20.8(s)0(e)19.9(s)-254.3(in)-250(di)20.7(ff)20.9(er)19.7(en)19.7(t)-260.4(w)0(a)18.8(y)0(s)21(;)-254.7(th)20.7(us)15.3(,)]TJ 0 -1.1116 TD [(it)-336.5(is)-342(es)19.9(se)19.9(nt)20.7(ia)19.6(l)-346.8(t)0(o)-336.4(s)0(t)15.1(u)0(d)20.8(y)-346.7(im)19.5(mu)19.6(ne)-337.4(re)19.7(sp)21(on)20.8(se)19.9(s)-346.5(i)0(n)-336.4(d)0(e)13.9(t)0(a)19.6(i)0(l)-336.5(t)0(o)-336.4(e)0(n)19.7(s)0(u)21(r)0(e)]TJ T* [(th)15(at)-337.6(ef)19.7(c)19.8(ie)19.5(nt)-336.4(st)15.1(ra)19.7(te)19.6(gi)20.7(es)-337.2(to)-336.4(ci)13.8(rc)19.7(um)19.6(ve)19.7(nt)-336.4(im)19.5(mu)19.6(ne)-337.4(re)19.7(sp)15.3(on)20.8(se)19.9(s)-346.5(a)0(r)19.7(e)]TJ 0 -1.1174 TD [(de)13.9(ve)19.7(lo)20.7(pe)19.7(d.)]TJ 1.0137 -1.1116 TD [(The)-305.2(complement)-305.2(system)-302.5(also)-299.2(plays)-306.1(a)-301.8(critical)-300.8(role)-305.2(in)-301.8(AdV)]TJ -1.0137 -1.1116 TD [(immune)-396.3(responses)-391.8(with)-391.4(effects)-391.2(mediated)-393.9(through)-393.7(the)-390.5(clas-)]TJ T* [(sical)-272.8(and)-269.4(alternative)-270.7(complement)-270.7(pathway.)-273.7(The)-264.8(complement)]TJ 0 -1.1174 TD [(system)-337(appears)-339.3(to)-336.4(be)-337.4(related)-334(to)-336.4(humoral)-338.5(immune)-332.9(responses)]TJ 0 -1.1116 TD [(to)-422.8(the)-419.3(vector)-418(capsid)-417.8(or)-422.6(the)-419.3(encoded)-420.1(transgene)-422.3(\(Appledorn)]TJ /F7 1 Tf T* [(et)-303(al.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-297.2(2008\).)-302.7(IgM)-303.7(isotype)-302.7(neutralization)-308.7(of)-301.7(virions)-307.2(activates)]TJ -2.0677 -1.1174 TD [(the)-643.9(classical)-648.1(complement)-645(pathway)-644.6(hampering)-647.1(receptor)]TJ 0 -1.1116 TD [(ligand)-301.8(interactions)-299.2(with)-299.3(the)-298.3(target)-302.9(cell)-295(\(Xu)]TJ /F7 1 Tf 17.5901 0 TD [(et)-297.2(al.)]TJ /F4 1 Tf 2.0562 0 TD [(,)-297.2(2013\).)-296.9(On)]TJ -19.6464 -1.1116 TD [(the)-528.7(other)-530.9(side,)-527.3(AdV-induced)-528.9(thrombocytopenia)-529.6(has)-528.4(been)]TJ 0 -1.1174 TD [(demonstrated)-444.2(to)-434.3(be)-435.3(dependent)-434(on)-434.2(factor)-441(B)-434.1(and)-436.4(C3)-429.5(of)-439.9(the)]TJ 0 -1.1116 TD [(alternative)-564.4(complement)-564.4(pathway,)-561.6(and)-563.2(AdVs)-558.9(mediate)-559.9(in-)]TJ T* [(duction)-285.6(of)-278.6(the)-286.8(nuclear)-282(factor-kappaB)-285(\(NF-)]TJ /F8 1 Tf 17.1178 0 TD (j)Tj /F4 1 Tf .5529 0 TD [(B\))-279.7(upon)-280.9(binding)]TJ -17.6708 -1.1174 TD [(to)-601.3(C3)-596.5(\(Appledorn)]TJ /F7 1 Tf 8.3631 0 TD [(et)-596.7(al.)]TJ /F4 1 Tf 2.3557 0 TD [(,)-596.7(2008\).)-602.2(In)-595.4(addition)-603.6(to)-595.6(macro-)]TJ -10.7188 -1.1116 TD [(phage)-7.8(s,)-275(DCs,)-284.9(and)-275.2(NK)-280.4(cells,)-282(binding)-284.4(of)-278.6(the)-281.1(CAR)-277(protein)-285.6(and)]TJ /F8 1 Tf T* (a)Tj /F4 1 Tf .5011 0 TD [(v-integrins)-566.3(on)-566.6(nonimmune)-566.6(cells)-566.6(also)-564.2(activates)-567.7(immune)]TJ -.5011 -1.1116 TD [(respon)-7.5(ses)-534(\(Liu)]TJ /F7 1 Tf 6.6813 0 TD [(et)-533.4(al.)]TJ /F4 1 Tf 2.2924 0 TD [(,)-533.3(2005;)-535.5(Schoggins)]TJ /F7 1 Tf 8.294 0 TD [(et)-533.4(al.)]TJ /F4 1 Tf 2.2981 0 TD [(,)-527.6(2005\).)-533(In)]TJ 9.843 0 0 9.843 313.0582 166.2236 Tm [(particular,)-623(CAR-media)-10.8(ted)-615.1(responses)-622.2(have)-623(been)-617.3(reported)]TJ 0 -1.1116 TD [(in)-561(epithelial)-568.1(cells)-560.8(\(Tamanini)]TJ /F7 1 Tf 12.8038 0 TD [(et)-562.2(al.)]TJ /F4 1 Tf 2.3212 0 TD [(,)-562.1(2006\))-558.4(and)-557.4(integrin-)]TJ -15.125 -1.1116 TD [(mediated)-595.5(responses)-593.4(in)-589.8(kidney)-589.6(epithelium-derived)-596.5(\(REC\))]TJ 0 -1.1174 TD [(cells,)-333.9(inducing)-332.8(expression)-329.8(of)-330.5(CXCL10)-333.3(\(IP-10\))-330(through)-324.6(NF-)]TJ /F8 1 Tf 0 -1.1116 TD (j)Tj /F4 1 Tf .5529 0 TD [(B)-336.2(i)0(n)-330.6(a)0(n)-337.4(RGD)-334.4(motif-dependent)-338.4(manner)-338.4(\(Liu)]TJ /F7 1 Tf 18.2122 0 TD [(et)-331.8(al.)]TJ /F4 1 Tf 2.0908 0 TD [(,)-331.7(2005\).)]TJ -19.8422 -1.1116 TD [(These)-423.5(anti-AdV)-426.6(innate)-423.9(immune)-419.3(responses)-426.3(are)-420.3(linked)-422.7(to)]TJ -1.0137 -1.1174 TD [(adapt)-8(ive)-361.7(immune)-361.7(responses)-363(through)-359.2(direct)-366.3(interactions)-368.3(and)]TJ 0 -1.1116 TD [(production)-352.2(of)-353.5(cytokines)-352.1(\(Ginsberg,)-349.3(1996;)-351.2(Appledorn)]TJ /F7 1 Tf 21.933 0 TD [(et)-354.8(al.)]TJ /F4 1 Tf 2.1138 0 TD (,)Tj -24.0468 -1.1116 TD [(2008\).)-279.6(When)-272.8(a)-278.7(cell)-271.9(is)-278.6(infected)-277.5(by)-272.9(AdVs,)-274.3(it)-278.9(releases)-278.1(type)-276.4(I)-271.8(\()]TJ /F8 1 Tf 23.7933 0 TD (a)Tj /F4 1 Tf -23.7933 -1.1174 TD (and)Tj /F8 1 Tf 1.9468 0 TD (b)Tj /F4 1 Tf .5529 0 TD [(\))-496.4(IFN.)-491.2(Plasmacyto)-9.9(id)-491.9(DCs,)-498(cDCs,)-500.3(and)-494(macrophages)]TJ -2.4997 -1.1116 TD [(produce)-580.2(IFN-)]TJ /F8 1 Tf 5.7482 0 TD (a)Tj /F4 1 Tf 1.0771 0 TD [(upon)-580.4(AdV)-575.3(recognition.)-582.7(The)-581.6(surrounding)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (286)Tj 43.6471 0 TD [(LOPEZ-GORDO)-336.9(ET)-338.7(AL.)]TJ ET endstream endobj 4 0 obj <> endobj 5 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 6 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(uninfected)-412.2(cells)-405.3(recognize)-412.1(IFN)-407.2(by)-399.6(IFN)-407.2(receptors)-410.7(and)-407.6(they)]TJ 0 -1.1174 TD [(induce,)-277.4(via)-269.5(the)-275.3(Jak-STAT)-277.8(signaling)-276.2(pathway,)-273.7(the)-269.5(expression)]TJ 0 -1.1116 TD [(of)-595.4(antiviral)-600.2(enzymes)-599.7(such)-598.6(as)-596.4(MxA,)-596(2)]TJ /F9 1 Tf 16.7953 0 TD ()Tj /F4 1 Tf .2477 0 TD (,5)Tj /F9 1 Tf .7488 0 TD ()Tj /F4 1 Tf .2534 0 TD (-oligoadenylate)Tj -18.0452 -1.1116 TD [(synthase,)-411.7(and)-407.6(protein)-412.3(kinase)-406.3(R)-411.1(\(Katze)]TJ /F7 1 Tf 16.3403 0 TD [(et)-412.4(al.)]TJ /F4 1 Tf 2.1714 0 TD [(,)-406.6(2002\).)-406.3(Also,)]TJ -18.5117 -1.1116 TD [(type)-299.4(I)-294.8(IFN)-292(induces)-298(upregulation)-298.1(of)-295.9(costimulatory)-300.4(molecules)]TJ 0 -1.1174 TD [(in)-388.2(DCs)-390.9(such)-391.3(as)-383.3(CD80,)-389.9(CD86,)-389.9(and)-390.4(CD40,)-389.9(leading)-390.4(to)-388.2(DCs)]TJ 0 -1.1116 TD [(maturation)-429.6(\(Vujanovic)]TJ /F7 1 Tf 9.7166 0 TD [(et)-424(al.)]TJ /F4 1 Tf 2.1829 0 TD [(,)-423.9(2009\).)-423.6(Moreover,)-430.1(IFN)-424.4(takes)]TJ -11.8996 -1.1116 TD [(part)-351.2(in)-347.9(B)-347.7(cells)-354.5(activation)-349.1(for)-348.8(antibody)-350.1(production.)-355.7(Type)-346.6(II)]TJ 0 -1.1174 TD [(IFN)-407.2(\(IFN-)]TJ /F8 1 Tf 4.2795 0 TD (c)Tj /F4 1 Tf .4377 0 TD [(\))-398.5(i)0(s)-405.3(a)0(n)-400.8(immunoregulatory)-408.6(cytokine)-403.1(secreted)-405(by)]TJ -4.7172 -1.1116 TD [(Th1-type)-276.2(T)-278.8(CD4)]TJ /F9 1 Tf 6.8944 0 TD (+)Tj /F4 1 Tf .9907 0 TD [(cells,)-276.3(T)-278.8(CD8)]TJ /F9 1 Tf 5.3104 0 TD (+)Tj /F4 1 Tf .9907 0 TD [(cells,)-276.3(and)-275.2(NK)-274.6(cells.)-276.3(IFN-)]TJ /F8 1 Tf -14.1862 -1.1116 TD (c)Tj /F4 1 Tf .8294 0 TD [(induces)-390.1(the)-390.5(expression)-393.2(of)-393.8(major)-388.1(histocompatibility)-398.6(com-)]TJ -.8294 -1.1174 TD [(plex)-420.4(class)-416.5(I)-415.8(\()-81.7(MHC-I\))-424(on)-411.1(nearly)-418(all)-419.4(cells)-416.8(and)-419.2(major)-416.9(histo-)]TJ 0 -1.1116 TD [(compatibility)-496.7(complex)-489.5(class)-491.4(II)-491.7(\()-81.7(MHC-II\))-494.2(on)-491.8(professional)]TJ T* [(antigen)-390.4(presenting)-382(cells)-388(\(APCs\))-382.5(promoting)-385.8(antigen)-384.7(pr)15.1(es)19.9(en)19.7(-)]TJ T* [(ta)13.8(ti)20.6(on)-347.8(to)-353.7(he)19.7(lp)20.7(er)-354.7(T)-365.2(C)0(D)18.9(4)]TJ /F9 1 Tf 9.5611 0 TD (+)Tj /F4 1 Tf 1.0771 0 TD [(ce)18.5(ll)14.8(s,)-349.9(an)19.7(d)-364(i)0(t)-353.8(a)0(l)19.5(s)0(o)-347.6(a)0(c)12.8(t)0(i)20.6(v)0(a)19.7(t)0(e)19.6(s)-363.8(ma)18.4(cr)19.7(o-)]TJ -10.6382 -1.1174 TD [(ph)15.1(ag)19.7(es)-314.2(\(G)20(at)19.5(to)20.7(ni)]TJ /F7 1 Tf 6.6525 0 TD [(et)-314.5(al)20.7(.)]TJ /F4 1 Tf 2.0447 0 TD -.0208 Tc [(,)-346.8(2)-20.8(00)-20.8(6\))-20.8(.)]TJ -7.6834 -1.1116 TD 0 Tc [(Dendritic)-359.1(cells)-353.5(have)-352.3(been)-358.1(shown)-351.8(to)-353.7(engulf)-353.5(infected)-358.1(cells)]TJ -1.0137 -1.1116 TD [(and)-263.7(present)-269.1(antigens)-264.6(to)-261.5(naive)-267.1(T)-261.5(CD8)]TJ /F9 1 Tf 14.8888 0 TD (+)Tj /F4 1 Tf .9849 0 TD [(cells)-261.3(through)-267(MHC-I)]TJ -15.8738 -1.1174 TD (\(Albert)Tj /F7 1 Tf 3.237 0 TD [(et)-343.3(al.)]TJ /F4 1 Tf 2.1023 0 TD [(,)-343.3(1998\).)-337.2(At)-343(the)-338.7(same)-347.6(time,)-338.8(APCs)-345.8(present)-344(anti-)]TJ -5.3392 -1.1116 TD [(gens)-327.9(to)-330.6(Th1-type)-328.1(T)-324.8(CD4)]TJ /F9 1 Tf 10.2638 0 TD (+)Tj /F4 1 Tf 1.0483 0 TD [(cells)-330.4(through)-324.6(MHC-II)-331.9(and)-327(upon)]TJ -11.3121 -1.1116 TD [(activation)-372.1(they)-368.6(produce)-367.1(IL-2.)-371.8(If)-365(the)-367.5(T)-370.9(CD8)]TJ /F9 1 Tf 18.0912 0 TD (+)Tj /F4 1 Tf 1.0828 0 TD [(cell)-369.9(receives)]TJ -19.1741 -1.1174 TD [(both)-545.9(antigen)-545.9(presence)-548.9(and)-545.9(IL-2)-546.9(signal,)-546.9(it)-543.9(gets)-546.9(activated)]TJ 0 -1.1116 TD [(\()-127.8(Jankovic)]TJ /F7 1 Tf 4.4753 0 TD [(et)-458.5(al.)]TJ /F4 1 Tf 2.2175 0 TD [(,)-452.7(2001\).)-452.4(Once)-456.9(the)-453.8(T)-457.3(CD8)]TJ /F9 1 Tf 11.1105 0 TD (+)Tj /F4 1 Tf 1.1692 0 TD [(cell)-456.2(interacts)]TJ -18.9725 -1.1116 TD [(with)-241.7(an)-239.5(infected)-242.9(cell,)-246.6(mainly)-239.6(recognizing)-240.5(conserved)-243.6(epitopes)]TJ 0 -1.1174 TD [(in)-273(hexon)-277.4(protein)-274(\(Olive)]TJ /F7 1 Tf 9.7281 0 TD [(et)-274.2(al.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-274.1(2002;)-270.6(Leen)]TJ /F7 1 Tf 5.3623 0 TD [(et)-274.2(al.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-268.4(2004;)-276.4(Tang)]TJ /F7 1 Tf -19.1568 -1.1116 TD [(et)-383.6(al.)]TJ /F4 1 Tf 2.1426 0 TD [(,)-383.6(2006\),)-377.5(it)-382.6(begins)-382.1(a)-382.4(cytotoxic)-387(response)-385.1(leading)-384.7(to)-376.7(ap-)]TJ -2.1426 -1.1116 TD [(optosis)-238(of)-238.3(the)-240.7(infected)-237.2(cell)-237.4(\(Schumacher)]TJ /F7 1 Tf 16.3057 0 TD [(et)-239.6(al.)]TJ /F4 1 Tf 1.9986 0 TD [(,)-233.8(2004\).)-239.3(On)-233.5(the)]TJ -18.3043 -1.1116 TD [(other)-358.1(hand,)-354.6(Th2-type)-362.6(T)-353.6(CD4)]TJ /F9 1 Tf 12.0263 0 TD (+)Tj /F4 1 Tf 1.0771 0 TD [(cells)-353.5(induce)-360.4(B)-353.5(cell)-358.3(matura-)]TJ -13.1033 -1.1174 TD [(tion)-338.7(and)-332.8(isotype)-331.5(switching)-340.4(\()-122(Jankovic)]TJ /F7 1 Tf 15.4936 0 TD [(et)-331.8(al.)]TJ /F4 1 Tf 2.0908 0 TD [(,)-337.5(2001\).)]TJ -16.5707 -1.1116 TD [(NAbs,)-568.1(mostly)-572.4(IgG)-568.6(isotype,)-571.1(interact)-571.3(with)-570(AdV)-569.5(capsid)]TJ -1.0137 -1.1116 TD [(proteins)-493.8(\(Gall)]TJ /F7 1 Tf 6.2723 0 TD [(et)-487.3(al.)]TJ /F4 1 Tf 2.2463 0 TD [(,)-487.2(1996;)-489.5(Sumida)]TJ /F7 1 Tf 7.0614 0 TD [(et)-487.3(al.)]TJ /F4 1 Tf 2.2463 0 TD [(,)-493(2005\).)-487(It)-486.1(was)]TJ -17.8263 -1.1174 TD [(reported)-368.3(that)-368.7(NAbs)-363.1(recognize)-371.8(mainly)-366.4(the)-361.7(hypervariab)-9.9(le)-360.6(re-)]TJ 0 -1.1116 TD [(gions)-431.7(\(HVRs\))-435.3(of)-428.4(the)-436.6(hexon)-427.1(protein)-435.3(\(Roberts)]TJ /F7 1 Tf 19.1395 0 TD [(et)-435.5(al.)]TJ /F4 1 Tf 2.1944 0 TD [(,)-429.6(2006;)]TJ -21.3339 -1.1116 TD (Abe)Tj /F7 1 Tf 2.1023 0 TD [(et)-435.5(al.)]TJ /F4 1 Tf 2.1944 0 TD [(,)-435.4(2009;)-431.9(Shiratsuchi)]TJ /F7 1 Tf 8.3458 0 TD [(et)-435.5(al.)]TJ /F4 1 Tf 2.1944 0 TD [(,)-435.4(2010;)-431.9(Bradley)]TJ /F7 1 Tf 7.0096 0 TD [(et)-435.5(al.)]TJ /F4 1 Tf 2.1945 0 TD (,)Tj -24.041 -1.1174 TD [(2012b\))-288.8(and)-292.4(to)-290.3(a)-284.5(lesser)-296.6(extent)-291.4(the)-286.8(ber)-287.6(knob)-292.4(domain)-291.4(\()-81.7(Myhre)]TJ /F7 1 Tf 0 -1.1116 TD [(et)-464.3(al.)]TJ /F4 1 Tf 2.2232 0 TD [(,)-464.2(2007;)-460.7(Bradley)]TJ /F7 1 Tf 7.0902 0 TD [(et)-464.3(al.)]TJ /F4 1 Tf 2.2232 0 TD [(,)-464.2(2012a;)-457.2(Yu)]TJ /F7 1 Tf 5.5812 0 TD [(et)-464.3(al.)]TJ /F4 1 Tf 2.2232 0 TD [(,)-458.4(2013\))-460.5(and)]TJ -19.3411 -1.1116 TD [(penton)-370.8(base)-369.4(proteins)-367.1(\(Yu)]TJ /F7 1 Tf 10.7649 0 TD [(et)-366.4(al.)]TJ /F4 1 Tf 2.1253 0 TD [(,)-366.3(2013\).)-366(AdV)-367.9(neutralization)]TJ -12.8902 -1.1116 TD [(prevents)-581.3(cell)-583(attachment)-581.7(and)-580.4(facilitates)-581.6(aggregation)-580.3(and)]TJ 0 -1.1174 TD [(phagocytosis)-499.2(mediated)-491.8(by)-491.8(opsonization)-493.8(\(Wohlfart,)-495(1988\).)]TJ 0 -1.1116 TD [(FcRs)-340.3(in)-342.1(macrophages)-340.3(and)-338.5(NK)-343.8(cells)-342(recognize)-343(NAbs)-340(bound)]TJ T* [(to)-342.1(AdV)-344.9(antigens,)-348.7(facilitating)-345.8(their)-341(phagocytic)-348.8(and)-338.5(cytolytic)]TJ 0 -1.1174 TD [(action,)-335.2(respectivel)-11.2(y)-329.4(\(Gattoni)]TJ /F7 1 Tf 11.9111 0 TD [(et)-331.8(al.)]TJ /F4 1 Tf 9.843 0 0 9.843 197.5747 275.8109 Tm [(,)-331.7(2006\).)]TJ -12.9881 -1.1116 TD [(In)-359.3(summary,)-360.1(AdV)-362.1(gene)-363.8(transfer)-362.3(vectors)-361.3(are)-362.7(subjected)-359.1(to)]TJ -1.0137 -1.1116 TD [(antiviral)-243.1(immune)-240.8(respon)-7.5(ses)-240.2(\(Fig.)-238.2(1\))-238.3(once)-242.9(administered)-242.7(to)-238.5(the)]TJ 0 -1.1174 TD [(patient.)-353.7(This)-351.1(process)-355.2(highly)-352.5(limits)-348(their)-352.5(efciency)-354.3(for)-354.6(gene)]TJ 0 -1.1116 TD [(therapy)-401.8(applications.)-394.9(Therefore,)-398.1(it)-394.1(is)-399.6(critical)-398.7(to)-394(understand)]TJ T* [(the)-430.8(immune)-430.8(response)-431.2(to)-428.5(AdVs)-432.2(and)-424.9(have)-432.9(strategies)-434.9(to)-422.8(cir-)]TJ 0 -1.1174 TD [(cumvent)-524(antiviral)-525.3(immune)-523(responses.)-521.9(These)-527.2(will)-518.3(be)-521.7(dis-)]TJ 0 -1.1116 TD [(cussed)-573(in)-572.5(the)-569(following)-569.8(sections,)-573.1(focusing)-568.6(on)-572.4(the)-569(main)]TJ T* [(limiting)-557.9(factors:)-558.3(NAbs)-553.1(against)-557.3(AdV)-552.2(proteins)-557.2(and)-557.4(CD8)]TJ /F9 1 Tf 23.7415 0 TD (+)Tj /F4 1 Tf -23.7415 -1.1116 TD [(cytotoxic)-340.9(T)-330.6(lymphocytes)-338.3(\(CTLs\))-338.1(against)-332.6(infected)-340.8(cells.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 149.7826 Tm [(Implications)-337.5(of)-336.6(Antiviral)-334.2(Immune)-335.8(Responses)-332.7(Against)]TJ 0 -1.2203 TD [(HAdV)-338(Vectors)-335.8(and)-331.9(Strategies)-339.5(to)-330.2(Circumvent)-337.4(Them)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 122.3999 Tm [(Since)-560.7(the)-557.5(tragic)-562.1(death)-560.9(of)-555.1(a)-560.9(patient)-557.6(participating)-565.6(in)-555.3(a)]TJ -1.0137 -1.1116 TD [(clinical)-560(gene)-553.9(therapy)-551.5(trial)-554.2(involving)-551.7(administration)-560.8(of)-549.3(a)]TJ 0 -1.1174 TD [(replication-incompetent)-800.4(HAdV-5)-792.5(vector)-792.4(\(Raper)]TJ /F7 1 Tf 21.4952 0 TD [(et)-786.8(al.)]TJ /F4 1 Tf 2.5458 0 TD (,)Tj -24.041 -1.1116 TD [(2003\),)-348.7(many)-352.4(efforts)-348.5(have)-352.3(been)-352.3(made)-347.8(to)-347.9(avoid)-352.4(antiviral)-346.8(im-)]TJ T* [(mune)-271.7(responses)-270.8(against)-269.3(AdV)-264.2(vecto)-8(rs)-266.9(to)-267.3(improve)-263.6(their)-271.8(safety)]TJ 0 -1.1174 TD [(and)-373.1(efcacy.)-372.7(Since)-370.7(the)-367.5(AdV)-367.9(vector)-371.9(recognition)-371.9(by)-365.1(the)-373.2(im-)]TJ 0 -1.1116 TD [(mune)-271.7(system)-273.7(depends)-274.8(on)-272.9(the)-269.5(existence)-273.8(of)-272.9(antigenic)-273(epitopes)]TJ 25.5097 67.9184 TD [(in)-244.2(the)-246.5(AdV)-247(proteins)-246.2(\(i.e.,)-245.2(NAbs)-247.9(recognize)-250.8(AdV)-247(proteins,)-249.6(and)]TJ 0 -1.1174 TD (CD8)Tj /F9 1 Tf 2.0505 0 TD (+)Tj /F4 1 Tf 1.1116 0 TD [(CTLs)-393.5(recognize)-400.6(infected)-398.4(cells\),)-392.5(most)-397.2(of)-393.8(the)-390.5(strate-)]TJ -3.1621 -1.1116 TD [(gies)-241.6(to)-244.2(circumvent)-246.4(the)-246.5(immunogenicity)-245.4(of)-244.1(HAdV)-248.9(vectors)-246.1(are)]TJ T* [(based)-335.9(on)-330.5(protein)-337.4(modications.)]TJ 1.0137 -1.1116 TD [(Functionally)-494(signicant)-503(HAdV-5-specic)-499.3(NAbs)-495.5(are)-500.9(di-)]TJ -1.0137 -1.1174 TD [(rected)-286.7(primarily)-289.1(against)-286.6(the)-286.8(HAdV-5)-285.7(hexon)-288.9(protein)-285.6(and)-280.9(to)-290.3(a)]TJ 0 -1.1116 TD [(lesser)-371.5(extent)-366.3(to)-370.9(ber)-368.2(and)-367.3(penton)-370.8(base)-369.4(proteins)-367.1(\(Gall)]TJ /F7 1 Tf 21.9099 0 TD [(et)-372.1(al.)]TJ /F4 1 Tf 2.1311 0 TD (,)Tj -24.041 -1.1116 TD [(1996;)-345.5(Sumida)]TJ /F7 1 Tf 6.0419 0 TD [(et)-349.1(al.)]TJ /F4 1 Tf 2.1081 0 TD [(,)-349(2005;)-351.2(Tian)]TJ /F7 1 Tf 5.4199 0 TD [(et)-349.1(al.)]TJ /F4 1 Tf 2.1081 0 TD [(,)-349(2011\).)-354.5(Despite)-350.8(sev-)]TJ -15.6779 -1.1174 TD [(eral)-294.8(groups)-294.4(successfully)-298.6(generated)-296.9(hexon-chimeric)-298(HAdV-5)]TJ 0 -1.1116 TD [(vectors)-660.8(that)-656.7(partially)-663.6(evaded)-660.9(anti-HAdV-5)-661.2(immune)-661.2(re-)]TJ T* [(sponses)-313.6(\(Gall)]TJ /F7 1 Tf 5.7943 0 TD [(et)-314.5(al.)]TJ /F4 1 Tf 2.0735 0 TD [(,)-314.5(1998;)-316.7(Roy)]TJ /F7 1 Tf 5.1434 0 TD [(et)-314.5(al.)]TJ /F4 1 Tf 2.0735 0 TD [(,)-314.5(1998;)-316.7(Ostapchuk)-318.3(and)]TJ -15.0847 -1.1174 TD [(Hearing,)-262.1(2001;)-259.1(Wu)]TJ /F7 1 Tf 7.9887 0 TD [(et)-262.7(al.)]TJ /F4 1 Tf 2.0217 0 TD [(,)-256.9(2002;)-264.8(Roberts)]TJ /F7 1 Tf 6.4278 0 TD [(et)-256.9(al.)]TJ /F4 1 Tf 2.0217 0 TD [(,)-256.9(2006;)-259.1(Bruder)]TJ /F7 1 Tf -18.4599 -1.1116 TD [(et)-418.2(al.)]TJ /F4 1 Tf 2.1772 0 TD [(,)-418.1(2012\),)-417.8(hexon)-415.6(pseudotyping)-423.4(appears)-419.9(to)-417(be)-418.1(a)-422.7(limited)]TJ -2.1772 -1.1116 TD [(strategy)-546.8(as)-544.6(it)-543.9(has)-545.7(been)-548.1(reported)-546.9(the)-540.2(formation)-548.1(of)-543.6(many)]TJ T* [(nonviable)-335(virions)-336.1(\(Youil)]TJ /F7 1 Tf 10.3559 0 TD [(et)-331.8(al.)]TJ /F4 1 Tf 2.0908 0 TD [(,)-331.7(2002\).)]TJ -11.433 -1.1174 TD [(The)-443.4(hexon)-438.6(protein)-446.8(\(Rux)-443.1(and)-442.2(Burnett,)-445.5(2000\))-443.2(contains)-443.2(7)]TJ -1.0137 -1.1116 TD [(HVRs)-312.3(\(Crawford-Miksza)-311.7(and)-309.7(Schnurr,)-311.6(1996\).)-308.4(Many)-311.7(groups)]TJ T* [(have)-634.5(exchanged)-642.4(HAdV-5)-637(HVRs)-634.8(with)-639.1(those)-634.4(from)-639.1(low-)]TJ 0 -1.1174 TD [(prevalent)-255.5(serotypes)-259.6(and)-252.1(demonstrated)-259.9(that)-259.3(the)-252.3(resultant)-260.1(AdV)]TJ 0 -1.1116 TD [(vector)-366.1(can)-362.7(evade)-366.1(HAdV-5)-366.3(immunity)-363(\(Roberts)]TJ /F7 1 Tf 19.272 0 TD [(et)-366.4(al.)]TJ /F4 1 Tf 2.1253 0 TD [(,)-360.5(2006;)]TJ -21.3973 -1.1116 TD (Abe)Tj /F7 1 Tf 2.1023 0 TD [(et)-435.5(al.)]TJ /F4 1 Tf 2.1945 0 TD [(,)-435.4(2009;)-437.6(Shiratsuchi)]TJ /F7 1 Tf 8.3458 0 TD [(et)-441.2(al.)]TJ /F4 1 Tf 2.2002 0 TD [(,)-435.4(2010\).)-435.1(Roberts)]TJ /F7 1 Tf 7.2515 0 TD [(et)-435.5(al.)]TJ /F4 1 Tf -22.0942 -1.1174 TD [(\(2006\))-323.3(showed)-331(that)-322.6(HAdV-5)-331.7(with)-328.1(all)-321.5(seven)-330.2(HVRs)-329.5(replaced)]TJ 0 -1.1116 TD [(with)-322.3(the)-327.1(corresponding)-327.6(ones)-327.9(from)-322.3(the)-327.1(rare)-323.4(serotype)-327.8(HAdV-)]TJ T* [(48)-244.1(could)-248.7(circumvent)-246.4(HAdV-5)-251.1(NAbs)-247.9(in)-244.2(both)-246.4(mice)-244.2(and)-246.4(rhesus)]TJ 0 -1.1174 TD [(monkeys.)-295.6(Further)-291(studies)-296.7(\(Bradley)]TJ /F7 1 Tf 14.2783 0 TD [(et)-291.5(al.)]TJ /F4 1 Tf 2.0505 0 TD [(,)-291.4(2012b\))-294.6(exchanged)]TJ -16.3288 -1.1116 TD [(only)-442.3(some)-444.3(HVRs)-444.7(and)-442.2(demonstrated)-450(that)-443.6(HAdV-5-specic)]TJ T* [(NAbs)-484(target)-487.2(multiple)-484(HVRs,)-488.5(suggesting)-484.3(that)-483.9(mutation)-489.6(or)]TJ T* [(replacement)-405.3(of)-393.8(all)-402.1(seven)-399.3(HVRs)-404.4(would)-398.2(probably)-401.7(be)-395(neces-)]TJ 0 -1.1174 TD [(sary)-437.3(to)-440.1(evade)-435.2(anti-HAdV-5)-442.3(immunity.)-441.3(However,)-441.4(in)-440.1(2012,)]TJ 0 -1.1116 TD (Coughlan)Tj /F7 1 Tf 4.3716 0 TD [(et)-481.5(al.)]TJ /F4 1 Tf 2.7186 0 TD [(demonstrated)-484.5(that,)-481.6(despite)-482.4(HAdV-5)-481.5(con-)]TJ -7.0902 -1.1116 TD [(taining)-377.9(all)-379.1(seven)-376.3(HVRs)-381.4(from)-379.9(HAdV-48,)-382.4(it)-376.8(displayed)-380.9(a)-376.6(de-)]TJ 0 -1.1174 TD [(creased)-870.3(hepatocyte)-868.4(transduction)-868.1(and)-862.7(accumulation)-871.9(in)]TJ 0 -1.1116 TD [(Kupffer)-533.8(cells,)-529.7(and)-528.6(it)-532.4(triggered)-530.8(a)-532.2(robust)-530.6(proinammatory)]TJ T* [(response)-350.5(not)-349(present)-349.8(with)-351.1(the)-344.4(wild-t)-7.8(ype)-344.3(HAdV-48)-350.1(\(Cough-)]TJ 0 -1.1174 TD (lan)Tj /F7 1 Tf 1.6473 0 TD [(et)-424(al.)]TJ /F4 1 Tf 2.1829 0 TD [(,)-418.1(2012\).)-423.6(In)-422.6(order)-421.3(to)-422.8(generate)-422.5(novel)-421.5(viable)-423.9(HVR-)]TJ -3.8302 -1.1116 TD [(chimeric)-324.8(vectors)-326.7(able)-323.6(to)-324.9(evade)-325.8(immune)-321.4(responses,)-331.8(it)-319.2(would)]TJ T* [(be)-268.3(necessary)-273.3(to)-267.3(use)-269.2(HVRs)-266.2(from)-270.5(other)-271.7(serotypes,)-268.8(and)-269.4(for)-268.2(that)]TJ T* [(it)-446(is)-451.4(essential)-451.1(to)-451.6(determine)-452.6(the)-448.1(viability)-455.2(of)-445.7(HVR)-455.3(replace-)]TJ 0 -1.1174 TD [(ments)-549.2(in)-543.7(AdV)-546.5(vectors)-551.4(based)-549(on)-543.6(the)-546(structural)-554.9(and)-545.9(bio-)]TJ 0 -1.1116 TD [(chemical)-383.6(constraints)-383(of)-382.3(the)-379(different)-386.8(HVRs)-381.4(that)-380.2(limit)-381.6(their)]TJ T* (manipulation.)Tj 1.0137 -1.1174 TD [(Regarding)-347.4(the)-350.2(immunogen)-7.9(icity)-346.9(of)-353.5(the)-350.2(ber)-345.2(protein,)-352.4(little)]TJ -1.0137 -1.1116 TD [(is)-267.1(known)-265.6(about)-271.8(the)-269.5(epitopes)-270.4(involved)-269.4(in)-267.3(ber)-264.6(recognition)-274(by)]TJ T* [(NAbs,)-360.7(although)-367.3(it)-359.6(is)-365(thought)-359.3(that)-362.9(antiknob)-367.3(NAbs)-363.1(represent)]TJ 0 -1.1174 TD [(the)-281.1(major)-290.2(population)-283.3(of)-284.4(antiber)-287.7(NAbs)-282.4(\()-81.7(Myhre)]TJ /F7 1 Tf 19.4332 0 TD [(et)-285.7(al.)]TJ /F4 1 Tf 2.0447 0 TD [(,)-279.9(2007;)]TJ -21.4779 -1.1116 TD (Bradley)Tj /F7 1 Tf 3.4846 0 TD [(et)-308.8(al.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-302.9(2012a;)-307.4(Yu)]TJ /F7 1 Tf 5.1146 0 TD [(et)-308.8(al.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-308.7(2013\).)-308.4(It)-307.6(has)-303.8(been)-312(reported)]TJ -12.7347 -1.1116 TD [(that)-316.8(ber)-316.4(pseudotyping)-319.7(of)-319(AdV)-321.8(vectors)-315.2(can)-322.4(lead)-317.9(to)-319.1(reduced)]TJ 0 -1.1174 TD [(AdV-associated)-252(innate)-251.1(\(Schoggins)]TJ /F7 1 Tf 14.0998 0 TD [(et)-251.2(al.)]TJ /F4 1 Tf 2.0101 0 TD [(,)-245.3(2005\))-247.4(and)-252.1(adaptive)]TJ -16.1099 -1.1116 TD [(immune)-304.1(responses)-305.4(\(Parker)]TJ /F7 1 Tf 11.0298 0 TD [(et)-303(al.)]TJ /F4 1 Tf 2.062 0 TD [(,)-302.9(2009;)-299.4(Roge)]TJ 4.8669 .0403 TD ()Tj .3859 -.0403 TD (e)Tj /F7 1 Tf .7488 0 TD [(et)-303(al.)]TJ /F4 1 Tf 2.062 0 TD [(,)-302.9(2010\).)]TJ -21.1554 -1.1116 TD [(Despite)-391.1(the)-396.3(C-terminal)-396.1(and)-390.4(shaft)-392.5(region)-393.8(heterogeneity,)-397.2(the)]TJ T* [(N-terminal)-401.7(region)-393.8(\(ber)-398.1(tail\))-398.7(that)-397.5(is)-393.8(bound)-397.2(to)-394(penton)-399.6(base)]TJ 0 -1.1174 TD [(protein)-297.1(presents)-298.8(high)-298.3(similarity)-296.1(among)-295.9(diverse)-303.7(AdV)-293(species)]TJ 0 -1.1116 TD (\(Tarassishin)Tj /F7 1 Tf 5.3508 0 TD [(et)-458.5(al.)]TJ /F4 1 Tf 2.2175 0 TD [(,)-458.4(2000\).)-458.2(Thus,)-452.3(designing)-460.4(chimeric)-463(AdV)]TJ -7.5682 -1.1116 TD [(vectors)-257.6(containing)-255.6(all)-252.4(proteins)-257.7(from)-253.2(HAdV-5)-256.9(but)-256.9(bers)-253.9(from)]TJ 0 -1.1174 TD [(other)-421.5(serotypes)-420.9(\(mainly)-419.3(species)-425.6(B)-416.8(and)-419.2(D\))-417.7(is)-422.6(a)-417(very)-420.2(inter-)]TJ 0 -1.1116 TD [(esting)-566.5(approach)-571(to)-566.8(retarget)-571.2(HAdV-5)-567.9(to)-566.8(different)-571.1(tissues)]TJ T* [(while)-411(circumventing)-411.1(antiviral)-410.1(preexisting)-412(immunity.)-412.5(Thus,)]TJ 0 -1.1174 TD [(several)-276(chimeric)-272.9(AdV)-270(vectors)-274.9(with)-270.5(tropism)-273.9(for)-273.9(different)-271.6(cell)]TJ 0 -1.1116 TD [(types)-277.3(such)-276.1(as)-279.6(HAdV-5/3)-276.5(\(Haviv)]TJ /F7 1 Tf 9.843 0 0 9.843 440.9007 89.5181 Tm [(et)-274.2(al.)]TJ /F4 1 Tf 2.0389 0 TD [(,)-274.1(2002;)-276.3(Kanerva)]TJ /F7 1 Tf 6.7504 0 TD [(et)-280(al.)]TJ /F4 1 Tf 2.0389 0 TD (,)Tj -24.041 -1.1116 TD [(2002;)-391.5(Volk)]TJ /F7 1 Tf 5.0628 0 TD [(et)-389.4(al.)]TJ /F4 1 Tf 2.1484 0 TD [(,)-395.1(2003;)-391.5(Ulasov)]TJ /F7 1 Tf 6.543 0 TD [(et)-389.4(al.)]TJ /F4 1 Tf 2.1484 0 TD [(,)-389.3(2007\),)-394.8(HAdV-5/11)]TJ -15.9025 -1.1174 TD (\(Havenga)Tj /F7 1 Tf 4.4004 0 TD [(et)-510.3(al.)]TJ /F4 1 Tf 2.2693 0 TD [(,)-504.5(2001)]TJ /F7 1 Tf 2.7589 0 TD (;)Tj /F4 1 Tf .8409 0 TD (Stone)Tj /F7 1 Tf 2.7877 0 TD [(et)-504.6(al.)]TJ /F4 1 Tf 2.2693 0 TD [(,)-504.5(2005;)-506.7(Wang)]TJ /F7 1 Tf 6.4451 0 TD [(et)-510.3(al.)]TJ /F4 1 Tf 2.2693 0 TD (,)Tj -24.041 -1.1116 TD [(2011b\),)-246.2(HAdV-5/16)-248.8(\(Havenga)]TJ /F7 1 Tf 12.4928 0 TD [(et)-245.4(al.)]TJ /F4 1 Tf 2.0044 0 TD [(,)-245.3(2001\),)-250.8(and)-246.4(HAdV-5/35)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(CIRCUMVENTING)-339.9(ANTIVECTOR)-341.1(IMMUNITY)]TJ 53.0113 0 TD (287)Tj ET endstream endobj 7 0 obj <> endobj 8 0 obj <>/Font<>/ProcSet[/PDF/Text/ImageC]/ExtGState<>>> endobj 9 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 62.022 220.9889 Tm 0 0 0 1 k 0 Tc 0 Tw (\(Havenga)Tj /F7 1 Tf 4.1297 0 TD [(et)-233.9(al.)]TJ /F4 1 Tf 1.9929 0 TD [(,)-233.8(2001\))-235.9(were)-232.2(generated.)-242.7(Interestingly,)-233.5(HAdV-)]TJ -6.1226 -1.1116 TD [(5/35)-425(and)-424.9(-5/11)-426.1(were)-428(assessed)]TJ /F7 1 Tf 12.8038 0 TD [(in)-422.8(vivo)]TJ /F4 1 Tf 3.3061 0 TD [(in)-428.5(murine)-423.8(and)-424.9(non-)]TJ -16.1099 -1.1174 TD [(human)-497.5(primate)-495.3(animal)-500(models)]TJ /F7 1 Tf 12.9248 0 TD (,)Tj /F4 1 Tf .743 0 TD [(showing)-492.3(reduced)-500.7(toxicity)]TJ -13.6678 -1.1116 TD [(and)-350(limited)-344.7(induction)-351.3(of)-342(inammato)-9(ry)-342(cytokines)-352.1(\(Ni)]TJ /F7 1 Tf 21.933 0 TD [(et)-349.1(al.)]TJ /F4 1 Tf 2.1081 0 TD (,)Tj -24.041 -1.1116 TD [(2005\).)-602.2(However,)-608.4(other)-600(studies)-607.8(showed)-601.7(that)-604.8(HAdV-5/35)]TJ 0 -1.1174 TD [(presented)-439.5(tropism)-440.9(for)-435.2(CD34)]TJ /F9 1 Tf 11.9399 0 TD (+)Tj /F4 1 Tf 1.1519 0 TD [(human)-439.9(hematopoietic)-441.2(stem)]TJ -13.0918 -1.1116 TD (cells)Tj /F7 1 Tf 2.4594 0 TD [(in)-612.9(vitro)]TJ /F4 1 Tf 3.8993 0 TD (\(Shayakhmetov)Tj /F7 1 Tf 6.9059 0 TD [(et)-614(al.)]TJ /F4 1 Tf 2.373 0 TD [(,)-614(2000\),)-613.7(monocytes,)]TJ -15.6376 -1.1116 TD [(granulocytes,)-411.8(and)-413.4(blast)-409.9(cells)-411.1(of)-411.1(human)-405.3(bone)-414.5(marrow)-407.2(\(Ro-)]TJ T* (gozhin)Tj /F7 1 Tf 3.0411 0 TD [(et)-308.8(al.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-308.7(2011\),)-314.2(and)-309.7(CD4)]TJ /F9 1 Tf 7.263 0 TD (+)Tj /F4 1 Tf 1.031 0 TD [(and)-309.7(CD8)]TJ /F9 1 Tf 3.8129 0 TD (+)Tj /F4 1 Tf 1.0252 0 TD [(T)-313.3(lymphocytes)]TJ /F7 1 Tf -18.241 -1.1174 TD [(in)-255.8(vitro)]TJ /F4 1 Tf 3.1909 0 TD (\(Zhang)Tj /F7 1 Tf 3.1506 0 TD [(et)-262.7(al.)]TJ /F4 1 Tf 2.0217 0 TD [(,)-256.9(2013b\).)-257.7(Since)-255.5(transduction)-263.4(of)-255.6(immune)]TJ -8.3631 -1.1116 TD [(cells)-480.2(can)-483.7(lead)-479.2(to)-480.4(immune)-482.7(responses,)-481.6(extensive)-480(character-)]TJ T* [(ization)-338.7(of)-330.5(chimeric)-336.3(AdV)-339.1(vectors)-332.5(is)-336.2(essential.)]TJ 1.0137 -1.1174 TD [(Other)-370.5(retargeting)-367.3(strategies)-371.6(such)-368.2(as)-371.8(the)-367.5(truncation)-370.8(or)-365(re-)]TJ -1.0137 -1.1116 TD [(moval)-422.7(of)-416.9(the)-425.1(ber)-420.1(knob)-419.1(domain)-423.8(and)-419.2(its)-423.8(replacement)-422.6(with)]TJ T* [(foreign)-250.8(trimerization)-255.8(motifs)-249.8(and)-252.1(heterologous)-251.7(peptides)-253.1(fused)]TJ 0 -1.1174 TD [(to)-336.4(the)-338.7(ber)-333.7(shaft)-340.6(are)-333.9(also)-339.6(recently)-335.1(being)-340.9(assessed)-339.8(\(ber)-334.7(de-)]TJ 25.504 16.7031 TD [(knobbing\))-286.5(\(Coughlan)]TJ /F7 1 Tf 8.9103 0 TD [(et)-285.7(al.)]TJ /F4 1 Tf 2.0447 0 TD [(,)-279.9(2010\).)-285.4(Despite)-287.4(that)-282.3(the)-281.1(removal)]TJ -10.955 -1.1116 TD [(of)-324.7(the)-321.4(ber)-322.2(knob)-321.2(domain)-320.2(results)-325.5(in)-324.9(a)-319(lower)-324.4(number)-320(of)-324.7(ber)]TJ 0 -1.1174 TD [(copie)-8(s)-237(per)-246.3(virion,)-240.7(leading)-246.4(to)-238.5(a)-244.2(less)-241.5(efcient)-248.5(production)-242.8(of)-244.1(the)]TJ 0 -1.1116 TD [(AdV)-540.7(vector,)-542.4(it)-532.4(has)-539.9(been)-542.4(shown)-536.1(that)-535.7(this)-540.1(approach)-542.2(may)]TJ T* [(contribute)-342(to)-330.6(evade)-337.3(NAbs)-334.3(\()-81.7(Myhre)]TJ /F7 1 Tf 14.2725 0 TD [(et)-337.6(al.)]TJ /F4 1 Tf 2.0965 0 TD [(,)-331.7(2007\).)]TJ -15.3554 -1.1174 TD [(Regarding)-577.8(the)-574.8(adaptive)-571.3(immunity)-576.1(mediated)-578.2(by)-572.4(CD8)]TJ /F9 1 Tf 22.7278 0 TD (+)Tj /F4 1 Tf -23.7415 -1.1116 TD [(CTLs,)-558.2(the)-557.5(response)-552.1(depends)-557(on)-555.1(viral)-554.1(antigenic)-555.2(epitopes)]TJ T* [(loade)-8(d)-542.5(i)0(n)-549.5(the)-551.8(MHC)-547.5(of)-549.3(the)-551.8(infected)-548.2(cell.)-551.8(High-capacity,)]TJ T* [(helpe)-8(r-dependent)-326.7(\(HD\))-328.6(vectors)-332.5(\(also)-323.3(called)-332.9(gutless)-325.5(vectors\))]TJ 0 -1.1174 TD [(bypass)-479.7(this)-471(problem)-471(\(Kochanek)]TJ /F7 1 Tf 13.8003 0 TD [(et)-470(al.)]TJ /F4 1 Tf 2.229 0 TD [(,)-475.7(1996\))-472(as)-469.7(they)-478(are)]TJ -16.0293 -1.1116 TD [(devoid)-445.6(of)-439.9(all)-442.5(viral)-444.6(genes,)-443.1(and)-442.2(therefore)-451.2(they)-437.7(are)-449.1(less)-443(im-)]TJ T* [(munogenic)-820(and)-816.6(allow)-814.2(long-term)-818.9(transgene)-819.7(expression)]TJ 0 -1.1174 TD [(\()-87.5(Maione)]TJ /F7 1 Tf 3.7208 0 TD [(et)-245.4(al.)]TJ /F4 1 Tf 2.0044 0 TD [(,)-239.6(2001;)-241.8(Ehrhardt)-241.6(and)-240.6(Kay,)-244.9(2002;)-241.8(Dudley)]TJ /F7 1 Tf 16.3172 0 TD [(et)-245.4(al.)]TJ /F4 1 Tf 2.0044 0 TD (,)Tj -24.0468 -1.1116 TD [(2004\).)-331.5(Furthermore,)-335.8(as)-331.5(in)-330.6(these)-336.1(vectors)-332.5(DNA)-334.2(is)-330.4(constituted)]TJ T* [(of)-359.3(stuffer)-360.1(DNA)-363(as)-354.5(part)-362.8(of)-353.5(the)-361.7(vector)-360.4(backbone)-357.9(to)-359.4(maintain)]TJ 0 -1.1174 TD [(optimum)-419.4(vector)-418(size,)-413.3(nonmethylated)-416.9(viral)-421.6(CpG-containing)]TJ ET q 420.92 0 0 318.501 96.775 413.745 cm /Im1 Do Q BT /F5 1 Tf 9.845 0 0 9.845 62.022 397.0204 Tm [(FIG.)-244.6(1.)]TJ /F4 1 Tf 4.0252 0 TD [(Innate)-244.6(and)-240.2(adaptive)-242.1(antiadenoviral)-249.6(immune)-240(responses.)]TJ /F5 1 Tf 21.9861 0 TD (\(1\))Tj /F4 1 Tf 1.4108 0 TD [(Activation)-244.1(of)-243.8(macrophages)-241.1(and)-246(natural)-245.7(killer)-243.7(\(NK\))-241.7(cells)]TJ -27.4222 -1.0135 TD [(by)-341.7(recognition)-347.7(of)-341.7(opsonized)-345.2(adenovirus)-340.5(\(AdV\))-346.3(through)-341.1(antibody-constant)-349.1(fraction)-344.6(receptor)-345.6(\(FcR\).)]TJ /F5 1 Tf 40.5344 0 TD (\(2\))Tj /F4 1 Tf 1.5087 0 TD [(Interleukin)-342(\(IL\)-1)]TJ /F8 1 Tf 7.1924 0 TD (b)Tj /F4 1 Tf -49.2356 -1.0135 TD [(maturation)-445.8(upon)-447.4(binding)-444.9(of)-445.4(arginine-glycine-aspartic)-454.2(acid)-449.9(\(RGD\))-445.2(motif)-444.1(in)-445.6(the)-447.7(AdV)-448(penton)-444.9(base)-443.8(with)-448.5(macrophage)]TJ /F8 1 Tf 48.7346 0 TD (b)Tj /F4 1 Tf .5528 0 TD (3)Tj -49.2874 -1.0135 TD (integrins.)Tj /F5 1 Tf 4.1749 0 TD (\(3\))Tj /F4 1 Tf 1.5836 0 TD [(Induction)-419.3(of)-416.6(IL-6)-419.8(and)-418.8(IL-12)-415(secretion)-421.5(in)-416.8(plasmacytoid)-420(dendritic)-420.6(cell)-415.5(\(pDC\))-421.4(upon)-412.8(AdV)-419.2(DNA)-420.1(recognition)]TJ -5.7585 -1.0077 TD [(through)-318.1(Toll-like)-322.9(receptor)-328.3(\(TLR\)-9.)]TJ /F5 1 Tf 14.8513 0 TD (\(4\))Tj /F4 1 Tf 1.4857 0 TD [(Dendritic)-323.6(cell)-323.4(\(DC\))-322.5(maturation)-324.9(through)-318.1(internalized)-322.5(immune)-320.6(complexes)-324.5(\(ICs\).)]TJ /F5 1 Tf 32.2824 0 TD (\(5\))Tj /F4 1 Tf -48.6194 -1.0135 TD [(Triggering)-323.6(of)-318.7(T)-318.9(cell)-317.6(immune)-320.6(responses)-321.7(upon)-320.7(binding)-318.2(of)-318.7(AdV)-321.3(ber)-321.7(shaft)-317.1(region)-324(to)-318.9(heparin-sensitive)-321.3(receptors)-323.4(on)-318.7(DCs.)]TJ /F5 1 Tf 48.6194 0 TD (\(6\))Tj /F4 1 Tf -48.6194 -1.0135 TD [(Interferon)-381(\(IFN\)-)]TJ /F8 1 Tf 6.9909 0 TD (a)Tj /F4 1 Tf .8753 0 TD [(production)-380(by)-376.3(activated)-382.7(pDCs,)-377.5(conventional)-378.7(DCs)-378.9(\(cDCs\),)-374.9(and)-378.4(macrophage)-384.3(and)-372.7(IFN-)]TJ /F8 1 Tf 35.0983 0 TD (a)Tj /F4 1 Tf .8753 0 TD [(recognition)-376.5(by)]TJ -43.8398 -1.0135 TD [(uninfected)-313.2(cells)-306.9(leading)-309.1(to)-307.4(a)-307.4(cellular)-311.4(antiviral)-311.4(state.)]TJ /F5 1 Tf 21.1972 0 TD (\(7\))Tj /F4 1 Tf 1.4742 0 TD [(Induction)-309.9(of)-307.2(CXCL10)-309.4(expression)-311.5(by)-307.2(AdV)-304.1(penton)-312.5(base)-305.6(RGD)-310.8(motif)]TJ -22.6714 -1.0077 TD [(binding)-370.1(to)]TJ /F8 1 Tf 4.578 0 TD (a)Tj /F4 1 Tf 7.3837 0 0 6.5625 112.0251 315.666 Tm (v)Tj 9.845 0 0 9.845 119.3385 317.3102 Tm (integrins.)Tj /F5 1 Tf 4.1289 0 TD (\(8\))Tj /F4 1 Tf 1.5375 0 TD [(Secretion)-369.6(of)-370.5(IFN-)]TJ /F8 1 Tf 7.2961 0 TD (a)Tj /F4 1 Tf .8695 0 TD (and)Tj /F8 1 Tf 1.8139 0 TD (b)Tj /F4 1 Tf .9214 0 TD [(by)-364.8(infected)-374.6(cells.)]TJ /F5 1 Tf 7.4343 0 TD (\(9\))Tj /F4 1 Tf 1.5375 0 TD [(Classical)-370.6(complement)-373.1(pathway)-367.3(activation)-371.1(by)]TJ -31.361 -1.0135 TD [(virion)-340.3(neutralization)-341.9(with)-333.4(IgM)-337.8(or)-341.7(recognition)-336.2(by)-336(IgG.)]TJ /F5 1 Tf 22.3316 0 TD (\(10\))Tj /F4 1 Tf 2.004 0 TD [(Thrombocytopenia)-338.7(related)-339(to)-336.2(alternative)-344.5(complement)-338.6(pathway)]TJ -24.3356 -1.0135 TD [(activation)-284.8(on)-278.4(AdVs.)]TJ /F5 1 Tf 8.3787 0 TD (\(11\))Tj /F4 1 Tf 1.9464 0 TD [(Major)-277.8(histocompatibility)-287.4(complex)-281.3(class)-277.8(II)-278.4(\()-87.4(MHC-II\))-280.2(induction)-281.3(on)-278.4(professional)-284.9(antigen)-280.3(presenting)]TJ -10.3251 -1.0077 TD [(cells)-312.7(\(APCs\))-306.9(by)-312.9(IFN-)]TJ /F8 1 Tf 8.6954 0 TD (c)Tj /F4 1 Tf .7486 0 TD [(signal)-306.7(promoting)-309.9(antigen)-309.1(presentation)-315.2(to)-307.4(helper)-313.7(T)-307.4(CD4)]TJ /F9 1 Tf 22.5505 0 TD (+)Tj /F4 1 Tf 1.025 0 TD (cells.)Tj /F5 1 Tf 2.4071 0 TD (\(12\))Tj /F4 1 Tf 1.9752 0 TD [(Induction)-309.9(of)-307.2(B)-307.2(cell)-311.9(maturation)]TJ -37.4017 -1.0135 TD [(and)-384.2(isotype)-382.6(switching)-385.6(through)-387.2(AdV)-384.7(antigen)-383.9(presentation)-384.3(by)-382(Th2-type)-384.7(T)-388(CD4)]TJ /F9 1 Tf 32.3285 0 TD (+)Tj /F4 1 Tf 1.0999 0 TD (cells.)Tj /F5 1 Tf 2.4762 0 TD (\(13\))Tj /F4 1 Tf 2.05 0 TD [(Activation)-388.1(of)-382(T)-382.2(CD8)]TJ /F9 1 Tf 8.8912 0 TD (+)Tj /F4 1 Tf 1.0999 0 TD (cells)Tj -47.9456 -1.0135 TD [(through)-306.5(AdV)-304.1(antigen)-309.1(presentation)-303.7(by)-307.2(DC)-303.2(via)-309.5(MHC-I.)]TJ /F5 1 Tf 22.1531 0 TD (\(14\))Tj /F4 1 Tf 1.9694 0 TD [(IL-2)-304.6(production)-310.9(by)-301.4(Th1-type)-304.1(T)-307.4(CD4)]TJ /F9 1 Tf 14.9895 0 TD (+)Tj /F4 1 Tf 1.025 0 TD [(cells)-306.9(upon)-303.4(AdV)-304.1(antigen)]TJ -40.1371 -1.0135 TD [(presentation)-263.4(by)-266.9(APCs)-258.8(through)-266.2(MHC-II,)-259.6(which)-266.2(activates)-267.3(T)-261.3(CD8)]TJ /F9 1 Tf 25.591 0 TD (+)Tj /F4 1 Tf .979 0 TD [(cells.)-264.2(BCR,)-268.5(B)-261.1(cell)-260(receptor;)-266.2(C3b,)-266.5(complement)-263.7(component)]TJ -26.5699 -1.0077 TD [(3b;)-331.4(CAR,)-337.4(coxsackie)-336.1(virus)-333.2(and)-338.1(adenovirus)-334.7(receptor;)-335.3(IFN)-337.6(R,)-333.6(interferon)-335.1(receptor;)-335.3(TCR,)-337.7(T)-330.4(cell)-340.7(receptor.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (288)Tj 43.6471 0 TD [(LOPEZ-GORDO)-336.9(ET)-338.7(AL.)]TJ ET endstream endobj 10 0 obj <>stream Adobed       m  s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz?N*S6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊5w*Evm mz;7m& Rt@H6*ږKclR>tTlUٱWfQvrݻLcc#ckȀ\n{fPWf]۽p)ͨM*i+˖8e-(By\Gx[[FTjB^m֙GYbxm[z|aʭr#tj-ZEQq]ڞ;ZGP!V_޳p鵱oik,$.L*SB~q\kuպ\@ܡUT}9$g(.^8$oqF]rչWf]vlUٱWf]v7Տc+WŦ$i7"_ڛpLvX6lUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWfW*D#PM7cA߮({徕Nգ:+_W+"½n#N.t*6mmūjsGyȨMf.+K 5ŴBHoFfgFU` 6*-7mZ,PuHvizH VދڙX\:7t;K˝Bx4ѤP\aK!rZͽ1TK-G@K]˺DB^k$Hd'r:aiVMAh[GW[yo%VĞt;rTEel!x;{KD% ]==NM$|UbjQZqL4- 2Ol(9-/$< 7[>c5͒7Ibe!ͶRGQ,(fHesh? pgjG "y63$i1mh{;*h{ $Un%qhB+ȠnkjyGrL>6D}H.] `O. \hzog' `Ust]8GGkeCbyW{I.8&rS+v(\ثb͊&P+V3@ZhJKm&(H4eBbWw?!ܜaRe |ڊYY%IYHc^ n/&cV*l3v\G9"/y ˺,(nn1WV 9E'"Jm0_:s1LzIJc&STzFXSHӬ𬋵z.f&:J<&4 WM!" 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[(Nevertheless,)-344.6(furthe)-7.8(r)-335.1(research)-341.5(needs)-341.7(to)-342.1(be)-337.4(done)-339.6(to)-336.4(describe)]TJ T* [(the)-453.8(pathways)-449.7(through)-445.5(which)-451.2(the)-448.1(AdV)-448.5(vectors)-453.4(trigger)-452.6(im-)]TJ 0 -1.1174 TD [(mune)-283.3(responses.)-285.8(There)-285.5(are)-282.1(more)-283.2(factors)-286.4(involved)-280.9(in)-278.8(cellular)]TJ 0 -1.1116 TD [(recognition)-429.5(that)-420.5(could)-421.5(also)-426(be)-423.8(implicated)-425.2(in)-422.8(promotion)-420.3(of)]TJ T* [(immune)-361.7(responses.)-354.9(These)-360.2(include)-361.6(alternative)-357.1(receptors)-358.9(and)]TJ T* [(coreceptors)-431.3(such)-425.8(as)-423.6(FcR)-425.8(\(Xu)]TJ /F7 1 Tf 12.6253 0 TD [(et)-429.7(al.)]TJ /F4 1 Tf 2.1887 0 TD [(,)-418.1(2008\),)-423.6(complement-3)]TJ -14.814 -1.1174 TD [(receptor)-369.5(\(CR-3\))-365.7(\(Xu)]TJ /F7 1 Tf 8.772 0 TD [(et)-366.4(al.)]TJ /F4 1 Tf 2.1253 0 TD [(,)-366.3(2008\),)-366(HSPGs)-363.8(and)-367.3(low-density)]TJ -10.8974 -1.1116 TD [(lipoprotein)-474.5(receptor-related)-479.9(protein)-475.6(\(LRP\))-468.3(\(Shayakhmetov)]TJ /F7 1 Tf T* [(et)-331.8(al.)]TJ /F4 1 Tf 2.0908 0 TD [(,)-331.7(2005\),)-325.7(complement)-334(receptor-1)-337.1(\(CR1\))-330.1(\(Carlisle)]TJ /F7 1 Tf 19.8652 0 TD [(et)-326(al.)]TJ /F4 1 Tf 2.085 0 TD (,)Tj -24.041 -1.1174 TD [(2009\),)-366(scavenging)-365.8(receptor-A)-366.7(\(SR-A\))-365.4(\(Khare)]TJ /F7 1 Tf 18.9725 0 TD [(et)-366.4(al.)]TJ /F4 1 Tf 2.1253 0 TD [(,)-360.5(2012\),)]TJ -21.0978 -1.1116 TD [(bridging)-245.2(molecules)-245.1(such)-241.5(as)-245.1(the)-240.7(coagu)-7.8(lation)-238.5(factor)-245.1(IX,)-242.6(X,)-241.6(and)]TJ T* [(VII)-378.5(and)-373.1(protein)-377.7(C)-376.5(\(Parker)]TJ /F7 1 Tf 11.1681 0 TD [(et)-377.9(al.)]TJ /F4 1 Tf 2.1369 0 TD [(,)-372(2006\),)-377.5(complement)-380.1(com-)]TJ -13.3049 -1.1174 TD [(ponent)-468.7(C4-binding)-473.1(protein)-464.1(\(C4BP\))-469.2(\(Shayakhmetov)]TJ /F7 1 Tf 21.8178 0 TD [(et)-464.3(al.)]TJ /F4 1 Tf 2.2232 0 TD (,)Tj -24.041 -1.1116 TD [(2005\),)-285.4(and)-280.9(IgM)-286.4(antibodies)-284.2(\(Xu)]TJ /F7 1 Tf 12.8384 0 TD [(et)-285.7(al.)]TJ /F4 1 Tf 2.0447 0 TD [(,)-285.7(2008\).)-279.6(Further)-285.2(studies)]TJ -14.8831 -1.1116 TD [(will)-334(have)-329.3(to)-330.6(be)-325.9(done)-328.1(in)-330.6(order)-329.1(to)-330.6(describe)-334.7(their)-329.4(inuence)-329.1(on)]TJ 0 -1.1174 TD [(the)-338.7(use)-332.6(of)-336.2(HAdV)-335.3(vectors)-332.5(for)-337.3(gene)-335(therapy)-332.7(applications.)]TJ 1.0137 -1.1116 TD -.0156 Tc [(Ap)6.3(ar)6.4(t)-506.4(f).6(r)6.4(o).6(m)-501.7(g).6(e)5.2(n).6(e)5.2(t).5(i)6.2(c)-507.4(en)6.3(gi)6.2(ne)5.2(er)6.4(in)6.3(g)-506.3(o).6(f)-500.5(HAd)6.3(V)-507.1(v)6.3(ec)5.2(to)6.3(rs,)-502.8(o)6.3(the)5.2(r)]TJ -1.0137 -1.1116 TD -.0192 Tc [(stra)-4.2(te)-4.2(gies)-383(such)-383.2(a)-4.2(s)-383(chem)-4.2(ic)-4.2(al)-383.3(m)-4.2(o)2.7(dica)-4.2(t)2.6(ions)-383(by)-383.2(addition)-383.2(of)-383.1(c)-4.2(a)1.6(t-)]TJ T* -.0167 Tc [(io)5.2(nic)-358.8(p)-.5(o)5.2(l)-.6(y)5.2(m)-1.7(ers)-357.4(o)-.5(r)-363.3(l)5.1(ip)5.2(id)-357.6(mo)5.2(lecu)5.2(les)-363.2(t)-.6(o)-357.6(s)-.3(h)5.2(i)-.6(eld)-363.4(A)4.4(dV)-358.5(vect)5.1(or)5.3(s)-363.2(a)-1.7(n)5.2(d)]TJ 0 -1.1174 TD -.0171 Tc [(pr)4.9(event)-600.1(t)4.7(hem)-601.2(f)-.9(r)4.9(o)-.9(m)-601.2(b)4.8(in)4.8(di)4.7(ng)-599.9(u)4.8(n)-.9(d)4.8(e)-2.1(si)4.7(red)-599.9(p)-.9(r)4.9(o)-.9(t)4.7(e)-2.1(i)4.7(n)-.9(s)-599.7(h)-.9(ave)-601.1(b)4.8(een)]TJ 0 -1.1116 TD -.0173 Tc [(wi)4.5(dely)-306.4(s)4.8(t)-1.2(ud)4.6(ied.)-303(Several)-306.5(v)4.6(ari)4.5(a)-2.3(n)4.6(t)-1.2(s)-306.2(o)4.6(f)-306.3(p)4.6(oly)4.6(e)-2.3(t)4.5(h)-1.1(y)4.6(l)-1.2(ene)-301.8(g)-1.1(ly)4.6(co)4.6(l)-306.5(\()-1.1(P)4.8(E)-2.3(G\))]TJ T* -.0175 Tc [(have)-336.5(been)-335.4(u)4.4(s)-1.1(ed,)-337.7(b)4.4(ut)-335.5(b)4.4(e)-2.5(t)4.3(t)-1.4(er)-341.1(s)4.6(h)-1.3(i)4.3(e)-2.5(l)4.3(d)-1.3(i)4.3(n)-1.3(g)-335.4(w)-2.2(as)-335.2(fo)4.4(und)-335.4(wit)4.3(h)-335.4(mu)4.4(lt)4.3(iva-)]TJ 0 -1.1174 TD -.0215 Tc [(l)-5.4(e)-.7(n)-5.3(t)-310.7(co)-5.3(po)-5.3(ly)-5.3(me)-6.5(rs)-310.4(of)-310.5(p)-5.3(o).4(l)-5.4(y).4([)]TJ /F7 1 Tf 9.659 0 TD 0 Tc (N)Tj /F4 1 Tf .6451 0 TD -.017 Tc [(-\()5(2-)5(hyd)4.9(ro)4.9(xy)4.9(pr)5(op)4.9(yl)4.8(\)met)4.8(hacry)4.9(l)-.9(amide])]TJ -10.3041 -1.1116 TD -.0173 Tc [(\(p)4.6(HPMA\))4.7(.)-343.3(S)4.8(h)-1.1(i)4.5(e)-2.3(l)4.5(d)-1.1(i)4.5(n)-1.1(g)-340.9(o)4.6(f)-340.9(H)-2(AdV)-341.8(v)4.6(ecto)4.6(rs)-340.7(with)-335.2(pHPMA)-341.8(s)-.9(ho)4.6(wed)]TJ T* -.0217 Tc [(a)-6.7(n)-472(in)-5.5(cr)-5.5(ea)-6.7(se)-6.7(d)-466.3(b)-5.5(io)-5.5(l)-5.6(o).2(g)-5.5(i).1(c)-6.7(a)-.9(l)-472.2(s).4(t)-5.6(a)-.9(b)-5.5(i)-5.6(li)-5.6(ty)-472.1(of)-472(t)-5.6(h).2(e)-473.2(v).2(e)-6.7(c)-.9(t)-5.6(o).2(r)-472(a)-6.7(nd)-472(a)-467.5(l)-5.6(on)-5.5(ge)-6.7(r)]TJ 0 -1.1174 TD [(p)-5.4(e)-.8(r)-5.4(s)-5.2(is)-5.2(te)-6.6(nc)-6.6(e)-392.5(i)-5.5(n)-391.3(b)-5.4(lo)-5.4(od)-5.4(,)-393.6(d)-5.4(ec)-6.6(re)-6.6(as)-5.2(ed)-397.1(li)-5.5(ve)-6.6(r)-391.3(t)-5.5(ra)-6.6(ns)-5.2(d)-5.4(u).3(c)-6.6(t).2(i)-5.5(o).3(n)-5.4(,)-393.6(an)-5.4(d)-391.3(t)-5.5(he)-6.6(r)-5.4(e)-.8(-)]TJ 0 -1.1116 TD -.0176 Tc [(fo)4.3(re)-382.7(a)-377(l)-1.5(o)4.3(w)-2.3(er)-381.5(immun)4.3(e)-382.7(resp)4.3(on)4.3(se)-377(\(Gr)4.4(e)-2.6(en)]TJ /F7 1 Tf 15.6376 0 TD -.0199 Tc [(et)-384(al.)]TJ /F4 1 Tf 2.0447 0 TD -.0217 Tc [(,)-382.2(2)-5.5(00)-5.5(4\))-5.5(.)-382.2(F)-5.4(ur)-5.5(th)-5.5(er)-5.5(-)]TJ -17.6823 -1.1116 TD [(m)-6.6(o).3(r)-5.4(e)-.8(,)-554.9(c)-6.6(oa)-6.6(te)-6.6(d)-552.6(H)-6.3(Ad)-5.4(V)-553.5(v)-5.4(ec)-6.6(to)-5.4(rs)-558.2(ha)-6.6(ve)-559.5(be)-6.6(en)-558.3(sh)-5.4(ow)-6.3(n)-552.6(t)-5.5(o)-552.6(b)-5.4(e)-553.7(l)-5.5(es)-5.2(s)]TJ 0 -1.1174 TD -.0167 Tc [(vu)5.2(lnerabl)5.1(e)-416.4(to)-415.2(reco)5.2(gn)5.2(it)5.1(io)5.2(n)-421(b)5.2(y)-421(p)5.2(reex)5.2(is)5.4(ti)5.1(ng)-415.2(NAbs)]TJ /F7 1 Tf 19.1337 0 TD -.0169 Tc [(in)-415.4(vitr)5.2(o)]TJ /F4 1 Tf 3.3809 0 TD -.0174 Tc (\(Ro-)Tj -22.5147 -1.1116 TD -.0154 Tc [(ma)5.4(nc)5.4(zu)6.5(k)]TJ /F7 1 Tf 3.738 0 TD -.0199 Tc [(et)-245.8(al.)]TJ /F4 1 Tf 1.9065 0 TD -.0172 Tc [(,)-245.3(1)4.7(99)4.7(9;)-243.1(Wang)]TJ /F7 1 Tf 5.4717 0 TD -.0199 Tc [(et)-245.8(al.)]TJ /F4 1 Tf 1.9065 0 TD -.0169 Tc [(,)-239.2(201)5(1a\))-242.6(a)3.9(nd)-242.6(b)5(y)-242.6(Kup)5(ffer)-242.6(c)3.9(el)4.9(ls)]TJ 9.843 0 0 9.843 310.8472 725.1588 Tm -.0218 Tc [(in)-276.3(t)-5.7(h)-5.6(e)-277.5(l)0(i)-5.8(v).1(e)-6.8(r)-276.3(\()-86.2(M)-.8(o)-5.6(k)]TJ /F7 1 Tf 6.9865 0 TD -.015 Tc [(et)-269.7(a)6.9(l)1.1(.)]TJ /F4 1 Tf 1.941 0 TD -.0174 Tc [(,)-274.3(2)4.5(00)4.5(5\))4.6(,)-274.3(l)-1.3(i)4.4(k)-1.2(ely)-271.9(b)4.5(ecau)4.5(se)-273.1(of)-271.9(t)4.4(h)-1.2(e)-273.1(h)-1.2(ampered)]TJ -8.9275 -1.1174 TD -.0154 Tc [(i)6.4(n).8(t)6.4(e)-.4(r)6.6(a)-.4(c)5.4(t).7(io)6.5(n)-707.7(o)6.5(f)-707.6(P)6.7(EG)5.7(yl)6.4(at)6.4(ed)-701.9(Ad)6.5(Vs)-701.7(an)6.5(d)-707.7(K)-.1(u)6.5(p).8(f)6.6(f).8(e)5.4(r)-707.6(c)5.4(e)-.4(l)6.4(l)-707.8(S)6.7(R)-.2(-)6.6(A)]TJ 0 -1.1116 TD -.0214 Tc [(\(H)-6.1(ai)-5.3(s)-5(m)-.7(a)]TJ /F7 1 Tf 3.7323 0 TD -.0199 Tc [(et)-470.4(al.)]TJ /F4 1 Tf 2.1311 0 TD -.0215 Tc [(,)-468.4(2)-5.3(00)-5.3(9\))-5.3(.)-468.4(H)-6.2(ow)-6.2(ev)-5.3(er)-5.3(,)-468.4(o)-5.3(th)-5.3(er)-471.8(f)-5.3(a)-.7(c)-6.5(t).3(o)-5.3(r).5(s)-471.7(c)-6.5(ou)-5.3(ld)-471.8(b)-5.3(e)-467.3(a)-6.5(f).5(-)]TJ -5.8634 -1.1116 TD -.0175 Tc [(f)4.5(e)-2.5(cti)4.3(n)-1.3(g)-479.4(l)-1.4(i)4.3(v)-1.3(er)-485.1(t)4.3(r)-1.3(ansd)4.4(ucti)4.3(on)-479.4(of)-479.3(th)4.4(e)-486.3(c)3.3(oated)-485.1(H)3.6(Ad)4.4(V)-480.2(s)-1.1(uch)-479.4(a)-2.5(s)-479.2(t)-1.5(h)4.4(e)]TJ T* -.0213 Tc [(li)-5.2(mi)-5.2(te)-6.3(d)-638.7(s).8(i)-5.2(z)-.5(e)-639.8(o).6(f)-638.6(t)-5.2(he)-639.8(s)-4.9(i).5(n)-5.1(u).6(s)-4.9(o).6(i)-5.2(d).6(a)-6.3(l)-638.8(en)-5.1(do)-5.1(th)-5.1(el)-5.2(ia)-6.3(l)-638.8(c)-.5(e)-6.3(l).5(l)-5.3(s).8()-638.6(f)-5.1(en)-5.1(es)-4.9(tr)-5.1(ae)]TJ 0 -1.1174 TD -.0171 Tc [(\()4.9(H)-1.8(o)4.8(fherr)]TJ /F7 1 Tf 3.7323 0 TD -.0199 Tc [(et)-389.8(al.)]TJ /F4 1 Tf 2.0505 0 TD -.0173 Tc [(,)-383.6(2)4.6(00)4.6(8\).)-377.8(Th)4.6(e)-388.2(u)4.6(se)-382.4(of)-381.2(PEGylated)-381.3(H)-2(AdV)-382.1(v)-1.1(ect)4.5(o)-1.1(r)4.7(s)]TJ -5.7827 -1.1116 TD -.0156 Tc [(r)6.4(e)-.6(s)6.5(u).6(lt)6.2(ed)-333.5(in)-333.5(de)5.2(cr)6.4(ea)5.2(se)5.2(d)-339.2(l)6.2(ev)6.3(el)6.2(s)-339(o).6(f)-333.4(I).6(L)5.2(-).6(6)-333.5(p).6(r)6.4(o).6(d)6.3(u).6(c)5.2(t).4(io)6.3(n)]TJ /F7 1 Tf 18.8227 0 TD -.0215 Tc [(in)-345.1(vi)-5.4(tr)-5.1(o)]TJ /F4 1 Tf 3.2197 0 TD .0644 Tc [(\(M)79.7(o)86.3(k)]TJ /F7 1 Tf -22.0424 -1.1116 TD -.0199 Tc [(et)-458.9(al.)]TJ /F4 1 Tf 2.1196 0 TD .4394 Tc [(,2)455.6(0)461.3(0)455.6(5)461.3(\)).6(a)454.4(n)461.3(do)455.6(fI)455.6(L)460.2(-)455.6(6a)460.2(n)455.6(d).6(I)461.4(L)454.4(-)461.4(1)455.6(2)]TJ /F7 1 Tf 13.1494 0 TD -.015 Tc [(i)6.8(n)-453.8(vi)6.8(vo)]TJ /F4 1 Tf 3.26 0 TD -.017 Tc [(\(Cro)4.9(yl)4.8(e)]TJ /F7 1 Tf 3.3867 0 TD -.015 Tc [(et)-454(a)6.9(l)1(.)]TJ /F4 1 Tf 2.1253 0 TD 0 Tc (,)Tj -24.041 -1.1174 TD -.0166 Tc [(2)5.3(0)-.4(0)5.3(0)-.4(\))5.4(.)-492.3(Mo)5.3(reo)5.3(v)-.4(er,)-492.3(c)4.2(oated)-495.7(H)4.5(Ad)5.3(V)-496.6(v)5.3(ecto)5.3(rs)-489.8(in)5.3(du)5.3(ce)-491.2(lo)5.3(wer)-495.7(I)5.4(L-)5.4(6)]TJ 0 -1.1116 TD -.0157 Tc [(l)6.1(e)-.7(v)6.2(e)-.7(l)6.1(s)-437.1(in)-437.3(se)5.1(ru)6.2(m)-438.5(b)6.2(ec)5.1(au)6.2(se)-438.4(of)-437.2(d)6.2(e)-.7(c)5.1(r).5(e)5.1(a)-.7(s)6.4(e)-.7(d)-437.3(l)6.1(ev)6.2(el)6.1(s)-437.1(o).5(f)-437.2(s)6.4(ple)5.1(e)5.1(n)-437.3(Ad)6.3(V)]TJ T* -.0218 Tc [(up)-5.6(ta)-6.8(ke)-427.2(\(D)-6.5(e)-421.5(G)-6.5(ee)-6.8(st)]TJ /F7 1 Tf 7.4531 0 TD -.0199 Tc [(et)-424.3(al.)]TJ /F4 1 Tf 2.085 0 TD -.0215 Tc [(,)-422.3(2)-5.3(00)-5.3(5\))-5.3(.)-422.3(F)-5.1(ur)-5.3(th)-5.3(er)-5.3(mo)-5.3(re)-6.5(,)-422.3(s)-5.1(ev)-5.3(er)-5.3(al)-425.9(gr)-5.3(ou)-5.3(ps)]TJ -9.5381 -1.1174 TD -.0157 Tc [(s)6.4(u).5(c)5.1(c)-.7(e)5.1(ssf)6.3(ul)6.1(ly)-552.4(re)5.1(ta)5.1(rg)6.2(et)6.1(ed)-552.5(co)6.2(at)6.1(ed)-552.4(Ad)6.2(V)-559.1(v)6.2(ec)5.1(to)6.2(rs)-552.3(\(P)6.4(ar)6.3(ke)5.1(r)]TJ /F7 1 Tf 21.8178 0 TD -.0199 Tc [(et)-562.5(al.)]TJ /F4 1 Tf 2.2232 0 TD 0 Tc (,)Tj -24.041 -1.1116 TD -.0173 Tc [(2)4.6(0)-1.1(0)4.6(5)-1.1(;)-467.8(S)-1(tevens)4.8(on)]TJ /F7 1 Tf 7.0729 0 TD -.0156 Tc [(et)-466.1(al)6.2(.)]TJ /F4 1 Tf 2.1426 0 TD -.016 Tc [(,)-468.7(2)5.9(00)5.9(7;)-466.5(Mo)5.9(rr)6(iso)5.9(n)]TJ /F7 1 Tf 7.4012 0 TD -.0199 Tc [(et)-476.1(al.)]TJ /F4 1 Tf 2.1368 0 TD -.0219 Tc [(,)-474.6(2)-5.7(00)-5.7(8,)-474.6(2)-5.7(0)0(0)-5.7(9)0(;)]TJ -18.7536 -1.1116 TD -.0196 Tc (Wang)Tj /F7 1 Tf 2.6725 0 TD -.0156 Tc [(et)-350.9(al)6.2(.)]TJ /F4 1 Tf 2.0217 0 TD -.0217 Tc [(,)-359.2(2)-5.5(01)-5.5(0\))-5.5(.)-353.4(A)-6.4(l)-5.7(t).1(h)-5.5(o).2(u)-5.5(g).2(h)-356.9(i)-5.6(n)-356.9(s)-5.3(om)-6.7(e)-358(s).4(t)-5.7(u)-5.5(di)-5.6(es)-356.7(t)-5.6(h).2(e)-6.7(y)-356.9(p)-5.5(r).3(e)-6.7(s).4(e)-6.7(n).2(t)-5.7(e)-.9(d)]TJ -4.6942 -1.1116 TD -.0192 Tc [(simila)-4.2(r)-244.9(l)-3.2(evels)-244.7(o)]TJ 5.8634 0 TD -.0215 Tc [(f)-247.2(a)-6.5(nt)-5.4(it)-5.4(um)-6.5(or)-5.3(al)-253.1(ef)-5.3(c)-6.5(ac)-6.5(y)-247.2(\()-85.9(M)-6.2(o).4(r)-5.3(r).5(i)-5.4(s)-5.1(on)]TJ /F7 1 Tf 12.7347 0 TD -.0156 Tc [(et)-241.5(al)6.2(.)]TJ /F4 1 Tf 1.9122 0 TD -.0162 Tc [(,)-244.3(2)0(0)5.7(09\))-241.9(o)5.7(r)]TJ -20.5103 -1.1174 TD -.0165 Tc [(t)5.3(r)-.3(ansg)5.4(en)5.4(e)-468(e)-1.5(x)5.4(p)-.3(r)5.5(e)-1.5(ss)5.6(io)5.4(n)-472.6(\()5.5(Park)5.4(er)]TJ /F7 1 Tf 11.9917 0 TD -.015 Tc [(et)-465.5(a)6.9(l)1.1(.)]TJ /F4 1 Tf 2.1369 0 TD -.0162 Tc [(,)-468.9(2)5.7(005)5.7(;)-466.7(S).1(t)5.6(e)-1.2(v)5.7(e)-1.2(n)5.7(s).2(on)]TJ /F7 1 Tf 7.7756 0 TD -.0199 Tc [(et)-476.1(al.)]TJ /F4 1 Tf 2.1368 0 TD 0 Tc (,)Tj -24.041 -1.1116 TD -.0219 Tc [(20)-5.7(07)-5.7(;)-288.1(M)-.9(o)-5.7(r).1(r)-5.7(i)-.1(s)-5.5(o)-5.7(n)]TJ /F7 1 Tf 6.3242 0 TD -.0199 Tc [(et)-286.1(al.)]TJ /F4 1 Tf 1.9468 0 TD -.0172 Tc [(,)-285.6(2)4.7(00)4.7(8;)-283.4(Wang)]TJ /F7 1 Tf 5.5927 0 TD -.0199 Tc [(et)-286.1(al.)]TJ /F4 1 Tf 1.9468 0 TD -.0164 Tc [(,)-284.8(2)5.5(01)5.5(0\))-282.4(to)-276.7(un)5.5(mo)5.5(di)5.4(ed)]TJ -15.8104 -1.1116 TD -.0155 Tc [(w)5.6(i).6(l)6.3(d).7(-)6.5(t).6(yp)6.4(e)-242.4(H)5.6(AdV)5.6(-).7(5)6.4(,)-243.6(o)6.4(t).5(h)6.4(e)-.5(r)6.5(s)-241(ac)5.3(hi)6.3(ev)6.4(ed)-241.2(a)-242.4(g)6.4(re)5.3(at)6.3(er)-241.2(t)6.3(h).7(e)5.3(r).7(a)5.3(p).7(e)5.3(u).7(t)6.3(i).6(c)-242.4(e)5.3(ff)6.5(ec)5.3(t)]TJ 0 -1.1174 TD -.0167 Tc [(wit)5.1(h)-265.5(negl)5.1(ig)5.2(ibl)5.1(e)-266.6(si)5.1(de)-260.9(eff)5.3(e)-1.7(cts)-265.3(\()5.3(Et)5.1(o)]TJ /F7 1 Tf 12.608 0 TD -.0156 Tc [(et)-258.7(al.)]TJ /F4 1 Tf 1.9353 0 TD -.0219 Tc [(,)-267.2(2)-5.7(01)-5.7(0;)-270.8(Y)-6.6(a)-1.1(o)]TJ /F7 1 Tf 4.8266 0 TD -.015 Tc [(et)-263.9(a)6.9(l)1.1(.)]TJ /F4 1 Tf 1.9353 0 TD -.0219 Tc [(,)-267.2(2)-5.7(01)-5.7(0\))-5.7(.)]TJ -21.3052 -1.1116 TD -.0215 Tc [(De)-6.5(sp)-5.3(it)-5.4(e)-369.3(t)-5.4(he)-375.1(li)-5.4(mi)-5.4(te)-6.5(d)-368.2(r)-5.3(et)-5.4(ar)-5.3(g)-5.3(e)-.7(t)-5.4(i).3(n)-5.3(g)]TJ 12.441 0 TD -.0173 Tc [(ef)4.7(ciency)-369.7(i)4.5(n)-369.7(c)3.5(ompari)4.5(so)4.6(n)-369.7(w)3.8(it)4.5(h)]TJ -12.441 -1.1116 TD -.0217 Tc [(un)-5.5(mo)-5.5(di)-5.7(e)-6.7(d)-604.5(H)-.6(A)-6.4(d).2(V)-6.4(-).3(5)-5.5(,)-606.9(th)-5.5(e)-605.7(u).2(s)-5.3(e)-605.7(of)-604.5(P)-5.4(E)-1(G)-6.4(y).2(l)-5.7(a)-.9(t)-5.6(e)-.9(d)-604.5(A)-6.4(dV)-605.4(v)-5.5(e)-.9(c)-6.7(t).1(o)-5.5(r).3(s)]TJ 0 -1.1174 TD -.0156 Tc [(a)5.2(c)-.6(h)6.3(i).5(e)5.2(v).6(e)5.2(d)-506.3(lo)6.3(we)5.2(r)-506.2(h)6.3(ep)6.3(at)6.2(ic)-507.4(t)6.2(r).6(o)6.3(p).6(i)6.2(s).8(m)-507.5(a)5.2(nd)-500.5(re)5.2(du)6.3(ct)6.2(ion)-500.5(i).4(n)-506.3(l)6.2(iv)6.3(er)-500.5(an)6.3(d)]TJ 0 -1.1116 TD -.0216 Tc [(sp)-5.4(le)-6.6(en)-558.3(t)-5.5(o).3(x)-5.4(i).2(c)-6.6(i).2(t)-5.6(y)]TJ /F7 1 Tf 6.4797 0 TD -.015 Tc [(i)6.8(n)-551.7(vi)6.8(vo)]TJ /F4 1 Tf 2.8971 0 TD -.0156 Tc [(.)-554.7(M)5.4(or)6.4(eo)6.3(ve)5.2(r,)-548.9(ev)6.3(id)6.3(en)6.3(ce)-553.5(h)6.3(i).5(g)6.3(h).6(l)6.2(i).4(g)6.3(h).6(t)6.2(s)-552.2(th)6.3(e)]TJ -9.3768 -1.1116 TD -.0176 Tc [(p)4.3(o)-1.4(t)4.2(e)-2.6(n)4.3(t)-1.5(i)4.2(a)-2.6(l)-502.6(o)-1.4(f)-502.5(A)3.5(dV)-503.4(p)4.3(o)-1.4(l)4.2(y)-1.4(mer)-502.5(c)3.2(oat)4.2(i)-1.5(n)4.3(g)-502.5(st)4.2(rategies)-502.3(to)-502.5(circumv)4.3(e)-2.6(n)4.3(t)]TJ 0 -1.1174 TD -.0172 Tc [(p)4.7(r)-1(eex)4.7(i)-1.1(st)4.6(in)4.7(g)-335.1(i)-1.1(mmuni)4.6(ty)-335.1(t)4.6(o)-335.1(al)4.6(l)-335.2(v)-1(i)4.6(r)-1(al)-335.2(capsi)4.6(d)-335.1(pr)4.8(ot)4.6(ei)4.6(ns)-334.9(\(Romanczu)4.7(k)]TJ /F7 1 Tf 0 -1.1116 TD -.0185 Tc [(et)-353.8(al.)]TJ /F4 1 Tf 2.0217 0 TD -.0171 Tc [(,)-348.8(1)-.9(9)4.8(99;)-352.4(Cro)4.8(y)-.9(l)4.7(e)]TJ /F7 1 Tf 6.0995 0 TD -.0199 Tc [(et)-355.2(al.)]TJ /F4 1 Tf 2.0159 0 TD -.0216 Tc [(,)-359.1(2)-5.4(00)-5.4(0;)-362.6(De)-357.9(G)-6.3(e)-.8(e)-6.6(s).5(t)]TJ /F7 1 Tf 7.1536 0 TD -.0156 Tc [(et)-350.9(al)6.2(.)]TJ /F4 1 Tf 2.0217 0 TD -.0219 Tc [(,)-359.4(2)-5.7(00)-5.7(5;)-357.2(M)-6.6(o)0(k)]TJ /F7 1 Tf -19.3123 -1.1116 TD -.0199 Tc [(et)-378.2(al.)]TJ /F4 1 Tf 2.0389 0 TD -.0178 Tc [(,)-378.3(2)4.1(00)4.1(5;)-376.1(Hai)4(s)-1.4(ma)]TJ /F7 1 Tf 6.4969 0 TD -.0199 Tc [(et)-378.2(al.)]TJ /F4 1 Tf 2.0389 0 TD -.0168 Tc [(,)-377.3(2)5.1(00)5.1(9;)-375.1(Zen)5.1(g)]TJ /F7 1 Tf 5.5351 0 TD -.0199 Tc [(et)-378.2(al.)]TJ /F4 1 Tf 2.0389 0 TD -.0156 Tc [(,)-376.1(2)6.3(01)6.3(2\))6.4(.)-376.1(N)5.5(ev)6.3(er)6.4(-)]TJ -18.1488 -1.1116 TD -.0214 Tc [(th)-5.2(el)-5.4(es)-5(s)-5(,)-353.1(th)-5.2(e)-352(r)-5.2(ep)-5.2(or)-5.2(te)-6.4(d)-350.8(P)-5.1(EG)-357.4(im)-6.4(mu)-5.2(no)-5.2(ge)-6.4(ni)-5.3(ci)-5.3(ty)-356.6(co)-5.2(ul)-5.4(d)-350.8(h)-5.2(am)-6.4(pe)-6.4(r)-350.8(P)-5.1(E-)]TJ 0 -1.1174 TD -.0217 Tc [(Gy)-5.5(la)-6.7(te)-6.7(d)-333.8(A)-6.4(dV)-6.4(s)-333.6(e)-6.7(f)]TJ 7.2342 0 TD -.0198 Tc [(ca)-4.8(cy)-337.7(\(Shimizu)]TJ /F7 1 Tf 5.9613 0 TD -.0185 Tc [(et)-330.8(al.)]TJ /F4 1 Tf 1.9986 0 TD -.0162 Tc [(,)-330.6(2)5.7(01)5.7(2\))5.8(.)]TJ -14.1804 -1.1116 TD 0 Tc [(Despite)-460.2(the)-459.6(advances)-462.5(made)-463(in)-457.3(HAdV)-462(vectors)-465(to)-457.3(evade)]TJ -1.0137 -1.1116 TD [(anti-AdV)-668.5(immune)-667(responses,)-665.9(the)-667(current)-666.7(strategies)-671.1(are)]TJ 0 -1.1174 TD [(limited)-540.5(by)-537.8(the)-546(formation)-542.4(of)-537.8(nonviable)-542.4(virions)-543.4(following)]TJ 0 -1.1116 TD [(molecular)-452.6(engineering)-453.6(and)-453.7(by)-451.5(the)-453.8(limited)-448.4(knowledge)-456.8(and)]TJ T* [(characterization)-481.2(of)-468.7(capsid)-475.4(epitopes)-477.7(motifs)-474.4(responsible)-475.1(for)]TJ 0 -1.1174 TD [(cross-reactivity.)-607.5(Therefore,)-605.4(the)-603.6(use)-603.3(of)-601.2(low-seroprevalent)]TJ 0 -1.1116 TD [(HAdV)-519.6(serotypes)-518.8(has)-522.6(been)-519.3(proposed)-522.4(as)-515.8(an)-521.7(alternative)-524.1(to)]TJ T* [(hexon)-288.9(or)-284.4(ber-chimeric)-290.9(AdV)-287.3(vectors)-292.2(in)-284.6(order)-288.8(to)-284.5(circumvent)]TJ T* [(preexisting)-365.9(NAbs.)-372.2(More)-363.5(than)-368.6(15)-365.1(years)-370.5(ago,)-365(several)-368.2(studies)]TJ 0 -1.1174 TD [(showed)-290.7(that)-293.8(the)-292.6(alternate)-297.1(use)-292.3(of)-295.9(AdV)-293(vectors)-292.2(from)-293.5(different)]TJ 0 -1.1116 TD [(serotypes,)-366.7(even)-363.8(within)-365(the)-361.7(same)-370.6(AdV)-362.1(species,)-365.7(can)-368.5(circum-)]TJ T* [(vent)-328.2(anti-AdV)-328.7(humoral)-332.8(immunity)-328.4(\(Kass-Eisler)]TJ /F7 1 Tf 19.3469 0 TD [(et)-326(al.)]TJ /F4 1 Tf 2.085 0 TD [(,)-326(1996;)]TJ -21.4319 -1.1174 TD (Mastrangeli)Tj /F7 1 Tf 5.2298 0 TD [(et)-441.2(al.)]TJ /F4 1 Tf 2.2002 0 TD [(,)-441.2(1996;)-443.4(Mack)]TJ /F7 1 Tf 6.1341 0 TD [(et)-441.2(al.)]TJ /F4 1 Tf 2.206 0 TD [(,)-435.4(1997;)-443.4(Parks)]TJ /F7 1 Tf 6.0707 0 TD [(et)-441.2(al.)]TJ /F4 1 Tf 2.2002 0 TD (,)Tj -24.041 -1.1116 TD [(1999\).)-400.6(A)-405.1(study)-402.9(on)-405.4(the)-402(presence)-404.9(of)-405.3(NAbs)-403.4(against)-407.5(different)]TJ T* [(HAdV)-473.6(serotypes)-472.7(in)-474.6(the)-471.1(Belgian)-472.1(population)-479.1(reported)-472(high)]TJ 0 -1.1174 TD [(seroprevalence)-304.5(toward)-296.7(species)-298.9(A,)-299.1(C,)-293.6(and)-298.2(E,)-299.5(while)-295.8(low)-298(sero-)]TJ 0 -1.1116 TD [(prevalence)-253.1(toward)-244.9(species)-252.8(B)-244(and)-246.4(D,)-247.3(among)-249.8(which,)-247.3(serotypes)]TJ 9.843 0 0 9.843 310.8472 221.0456 Tm [(11,)-230.3(34,)-236(35,)-230.3(50)-238.3(\(species)-236.6(B\),)-231.3(43,)-236(and)-234.9(48)-232.6(\(species)-236.6(D\))-233.4(showed)-238.8(the)]TJ 0 -1.1174 TD [(lowest)-273.7(values)-268.1(\(Vogels)]TJ /F7 1 Tf 9.1522 0 TD [(et)-268.4(al.)]TJ /F4 1 Tf 2.0274 0 TD [(,)-274.1(2003\).)-268.1(This)-270.5(indicates)-272.8(that)-270.8(these)]TJ -11.1796 -1.1116 TD [(serotypes)-518.8(could)-519.4(be)-516(potentially)-516.2(used)-518(to)-520.7(evade)-515.9(preexisting)]TJ T* [(immunity.)-631.4(Vectors)-638.6(have)-634.5(been)-634.5(developed)-641.3(from)-633.4(multiple)]TJ T* [(HAdV)-381.4(serotypes)-380.6(with)-379.9(lower)-376.3(seroprevale)-10.9(nce)-380(than)-374.3(HAdV-5:)]TJ 0 -1.1174 TD [(HAdV-11)-361.6(\(Holterman)]TJ /F7 1 Tf 9.3365 0 TD [(et)-366.4(al.)]TJ /F4 1 Tf 2.1253 0 TD [(,)-360.5(2004;)-362.7(Stone)]TJ /F7 1 Tf 5.8979 0 TD [(et)-360.6(al.)]TJ /F4 1 Tf 2.1253 0 TD [(,)-360.5(2005;)-362.7(Ab-)]TJ -19.4851 -1.1116 TD (bink)Tj /F7 1 Tf 2.2866 0 TD [(et)-510.3(al.)]TJ /F4 1 Tf 2.2693 0 TD [(,)-510.3(2007\),)-504.2(HAdV-35)-511.4(\(Gao)]TJ /F7 1 Tf 10.857 0 TD [(et)-510.3(al.)]TJ /F4 1 Tf 2.2693 0 TD [(,)-504.5(2003;)-506.7(Sakurai)]TJ /F7 1 Tf -17.6823 -1.1116 TD [(et)-452.8(al.)]TJ /F4 1 Tf 2.2117 0 TD [(,)-446.9(2003,)-457.1(2009;)-449.1(Seshidhar)-455.5(Reddy)]TJ /F7 1 Tf 13.5987 0 TD [(et)-452.7(al.)]TJ /F4 1 Tf 2.2117 0 TD [(,)-452.7(2003;)-449.1(Vogels)]TJ /F7 1 Tf -18.0221 -1.1174 TD [(et)-447(al.)]TJ /F4 1 Tf 2.206 0 TD [(,)-452.7(2003;)-449.1(Barouch)]TJ /F7 1 Tf 7.2745 0 TD [(et)-452.7(al.)]TJ /F4 1 Tf 2.2117 0 TD [(,)-446.9(2004;)-449.1(Wu)-448(and)-453.7(Tikoo,)-448(2004;)]TJ -11.6922 -1.1116 TD (Abbink)Tj /F7 1 Tf 3.3982 0 TD [(et)-406.7(al.)]TJ /F4 1 Tf 2.1656 0 TD [(,)-400.8(2007;)-403.1(Brouwer)]TJ /F7 1 Tf 7.2342 0 TD [(et)-400.9(al.)]TJ /F4 1 Tf 2.1599 0 TD [(,)-400.8(2007;)-403.1(Sakurai,)-405.1(2008;)]TJ -14.958 -1.1116 TD (McVey)Tj /F7 1 Tf 3.6286 0 TD [(et)-625.5(al.)]TJ /F4 1 Tf 2.3845 0 TD [(,)-631.2(2010;)-627.7(Geisbert)]TJ /F7 1 Tf 7.8102 0 TD [(et)-631.3(al.)]TJ /F4 1 Tf 2.3903 0 TD [(,)-625.5(2011\),)-625.2(HAdV-49)]TJ -16.2136 -1.1174 TD (\(Lemckert)Tj /F7 1 Tf 4.4522 0 TD [(et)-268.4(al.)]TJ /F4 1 Tf 2.0274 0 TD [(,)-262.6(2006;)-270.6(Abbink)]TJ /F7 1 Tf 6.3299 0 TD [(et)-268.4(al.)]TJ /F4 1 Tf 2.0274 0 TD [(,)-262.6(2007\),)-268.1(HAdV-26,)-267.2(-48,)]TJ -14.837 -1.1116 TD [(and)-240.6(-50)-239.4(\(Abbink)]TJ /F7 1 Tf 6.8368 0 TD [(et)-239.6(al.)]TJ /F4 1 Tf 1.9986 0 TD [(,)-239.6(2007;)-241.8(Geisbert)]TJ /F7 1 Tf 6.6525 0 TD [(et)-239.6(al.)]TJ /F4 1 Tf 1.9986 0 TD [(,)-239.6(2011\),)-239.3(HAdV-7)]TJ -17.4865 -1.1116 TD (\(Nan)Tj /F7 1 Tf 2.5285 0 TD [(et)-533.4(al.)]TJ /F4 1 Tf 2.2924 0 TD [(,)-527.6(2003\),)-533(and)-528.6(HAdV-6)-533.3(\(Capone)]TJ /F7 1 Tf 13.8175 0 TD [(et)-527.6(al.)]TJ /F4 1 Tf 2.2866 0 TD [(,)-533.3(2006\).)]TJ -20.925 -1.1174 TD [(However,)-527.8(since)-526.1(the)-528.7(presence)-525.9(of)-526.3(NAbs)-524.3(depends)-528.2(on)-526.3(AdV)]TJ 0 -1.1116 TD [(exposure,)-325.4(which)-324.5(is)-324.7(closely)-326.9(related)-328.2(to)-324.9(geographical)-329.1(location,)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(CIRCUMVENTING)-339.9(ANTIVECTOR)-341.1(IMMUNITY)]TJ 53.0113 0 TD (289)Tj ET endstream endobj 14 0 obj <> endobj 15 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 16 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(se)19.9(ro)15.1(pr)20.9(ev)19.7(al)19.5(en)19.7(ce)-448(st)15.1(ud)20.8(ie)19.5(s)-455.9(i)0(n)-445.8(d)0(i)20.7(f)0(f)15.1(e)0(r)19.7(e)0(n)19.7(t)-456.2(sp)21(ec)18.5(i)15.1(c)-457.3(p)0(o)20.8(p)0(u)20.8(l)0(a)19.6(t)0(i)20.6(o)0(n)20.8(s)-461.7(ar)19.7(e)]TJ 0 -1.1174 TD [(ve)19.7(ry)-526.3(im)19.5(po)20.8(rt)20.7(an)13.9(t.)-523(Mo)19.9(re)19.7(ov)20.8(er)14(,)-533.3(b)0(e)19.7(t)0(t)20.6(e)0(r)-527.5(c)0(h)19.7(a)0(r)19.7(a)0(c)18.5(t)0(e)19.6(r)0(i)15(z)0(a)18.5(t)0(i)20.6(o)0(n)-526.3(o)0(f)-520.5(s)0(u)15.3(c)0(h)]TJ 0 -1.1116 TD [(se)19.9(ro)15.1(ty)20.7(pe)19.7(s)-300.4(i)0(n)-284.6(t)0(e)13.8(r)0(m)19.6(s)-294.6(of)-290.2(tr)15(op)20.8(is)20.9(m)-301.8(a)0(n)19.7(d)-294.8(sp)15.3(ec)18.5(i)20.9(ci)19.6(ty)20.7(,)-302.9(b)0(i)20.7(o)0(d)20.8(i)0(s)20.9(t)0(r)15(i)0(b)20.7(u)0(t)20.7(i)0(o)20.7(n)0(,)]TJ T* [(an)19.7(d)-323.6(t)0(o)20.7(x)0(i)15(c)0(i)19.5(t)0(y)-313.3(i)0(s)-313.2(y)0(e)19.7(t)-323.8(re)19.7(qu)20.8(ir)20.7(ed)-314.4(to)-313.3(de)13.9(si)20.9(gn)-313.2(sa)19.9(fe)-314.3(HA)19.1(dV)-314.1(ve)19.7(ct)19.5(or)15.1(s.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 670.3369 Tm [(Use)-334.1(of)-336.6(Nonhuman)-332.9(Adenoviral)-338(Vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 72 653.8959 Tm [(The)-408.8(idea)-415.8(about)-410(NHAdVs)-413.1(as)-412.1(vectors)-413.1(appeared)-410.9(in)-411.3(1990s,)]TJ -1.0137 -1.1116 TD [(with)-483.6(the)-488.4(assumption)-485.6(that)-483.9(they)-483.7(would)-484.6(be)-487.2(more)-484.8(useful)-485.7(for)]TJ T* [(vaccines)-382(and)-384.6(gene)-381.1(therapeutic)-380(approaches)-384.1(in)-382.5(human)-382.3(medi-)]TJ 0 -1.1174 TD [(cine)-294.8(than)-293.7(HAdV-based)-298(vectors.)-295.6(Design)-296.6(and)-298.2(characterization)]TJ 0 -1.1116 TD [(of)-635.7(NHAdV)-631(vectors)-637.7(was)-632.9(reviewed)-635.3(earlier)-639.2(\(Bangari)-634.3(and)]TJ T* [(Mittal,)-243(2006\),)-233.5(with)-241.7(a)-238.4(focus)-236.8(on)-238.3(vaccine)-242.9(vectors.)-238(In)-238.3(this)-240.6(review)]TJ 0 -1.1174 TD [(we)-442(focus)-438.4(on)-434.2(the)-442.3(progress)-435.7(in)-440.1(the)-436.6(development)-443.3(of)-439.9(NHAdV)]TJ 0 -1.1116 TD [(vectors)-338.2(\(Table)-332.8(1\))-336.2(for)-331.5(gene)-335(therapy.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 555.3069 Tm [(Canine)-333.6(AdV)-335.3(vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 72 538.866 Tm -.0245 Tc [(C)-9.3(a)-24.5(ni)-24.5(ne)-476(A)-24.5(d)1.2(V)-481.5(\()-24.5(ge)-24.5(nu)-24.5(s)]TJ /F7 1 Tf 8.6568 0 TD 0 Tc [(M)15.1(a)0(s)26.8(t)0(a)20.7(d)16.2(en)25.4(ov)25.4(ir)20.9(u)16.2(s)]TJ /F4 1 Tf 6.2666 0 TD [(,)-452.7(s)0(p)26.8(e)0(c)24.3(i)0(e)25.3(s)-455.9(CA)24.7(dV)-446.6(A)15.3(\))0(-)]TJ -15.9371 -1.1174 TD [(de)25.4(ri)26.5(ve)25.4(d)-571.3(v)16.2(ec)24.3(to)20.7(r)16.2(s)-571.1(a)15(r)0(e)-556.3(c)0(u)25.4(r)0(r)26.7(e)0(n)19.7(t)16.1(ly)-555.3(th)26.5(e)-572.5(b)16.2(es)25.6(t)-571.4(d)16.2(es)25.6(cr)19.7(i)16.1(b)0(e)25.4(d)-571.3(N)15.3(H)0(A)24.9(d)0(V)]TJ 0 -1.1116 TD [(ve)25.4(ct)25.3(or)26.6(s.)-280.8(U)15.3(p)-289.1(to)-278.8(9)16.2(0)0(%)-274(o)0(f)-278.6(t)0(h)26.5(e)-290.2(re)25.5(si)26.7(du)26.6(es)-279.6(in)26.5(vo)26.6(lv)26.5(ed)-279.8(i)16.1(n)-289.1(CA)24.7(dV)20(-)16.2(2)-289.1(b)26.8(er)]TJ T* [(ta)25.3(il)26.3(-p)20.9(e)15(n)0(t)26.5(o)0(n)-491.8(b)16.2(as)25.6(e)-503.4(i)0(n)26.5(t)0(e)25.3(r)0(a)19.7(c)15(ti)26.3(on)26.6(s)-502(a)0(r)25.5(e)-503.3(co)25.4(ns)26.8(er)19.7(v)16.2(e)0(d)-492.9(c)15(om)25.4(pa)25.4(re)25.5(d)-502.2(w)0(i)25.6(t)0(h)]TJ 0 -1.1174 TD [(HA)24.9(dV)25.7(-5)-543.6(\()16.2(S)0(c)25.6(h)0(o)26.6(e)0(h)19.7(n)]TJ /F7 1 Tf 8.2191 0 TD [(et)-539.1(al)20.7(.)]TJ /F4 1 Tf 2.2636 0 TD [(,)-550.6(2)16.2(00)20.8(8)16.2(\))0(.)-540.1(C)0(A)24.7(d)0(V)25.7(-)0(2)-543.6(b)16.2(in)26.5(ds)-543.4(t)16(o)-554(C)15.2(A)0(R)]TJ -10.4827 -1.1116 TD [(\(T)25.4(om)25.4(ko)]TJ /F7 1 Tf 3.5768 0 TD [(e)15(t)-410.2(al)20.7(.)]TJ /F4 1 Tf 2.1196 0 TD [(,)-406.6(1)0(9)20.8(9)16.2(7;)-399.7(S)16.3(o)0(u)20.8(d)16.2(ai)25.3(s)]TJ /F7 1 Tf 6.8022 0 TD [(e)15(t)-410.2(al)26.5(.)]TJ /F4 1 Tf 2.1138 0 TD [(,)-412.4(2)0(0)26.6(0)0(0)26.6(\))0(,)-401.9(b)16.2(ut)-399.7(it)-399.9(d)16.2(o)0(e)25.4(s)-415.6(n)16.2(o)0(t)]TJ -14.6124 -1.1116 TD [(co)25.4(nt)26.5(ai)25.3(n)-300.6(a)15(n)-300.6(i)16.1(nt)20.7(e)15(g)0(r)26.6(i)0(n)26.5(-)0(i)20.7(n)16.2(te)25.3(ra)25.5(ct)19.5(i)16.1(n)0(g)-284.4(R)0(G)24.7(D)-301.5(m)15(o)0(t)26.5(i)0(f)-284.5(i)0(n)-284.6(t)0(h)26.5(e)-301.8(p)16.2(e)0(n)19.7(t)16.1(on)-284.4(ba)25.4(se)]TJ 0 -1.1174 TD [(\(C)25.6(hi)26.5(ll)20.6(o)16.2(n)-225.7(an)25.4(d)-225.7(K)0(r)25.8(e)0(m)24.2(e)0(r)25.5(,)-228.1(2)16.2(0)0(0)20.8(1)16.2(\))-225.7(i)0(n)-215.4(c)15(on)26.6(tr)20.7(a)15(s)0(t)-215.2(w)15.3(it)26.3(h)-225.7(H)0(A)24.9(d)0(V)20(-)16.2(5)-225.7(\()0(G)25.8(r)0(e)19.7(b)16.2(er)25.5(,)]TJ 0 -1.1116 TD [(20)26.6(02)26.6(\).)-223.4(CA)24.7(dV)25.7(-2)-226.8(p)16.2(e)0(n)25.4(t)0(o)26.5(n)-237.2(ba)25.4(se)-222(ap)19.7(p)16.2(e)0(a)24.3(r)0(s)-220.8(t)0(o)-227(b)16.2(e)]TJ /F11 1 Tf 16.634 0 TD (*)Tj /F4 1 Tf .9849 0 TD [(20)26.6(%)-238.3(s)0(h)26.8(o)0(r)26.6(t)0(e)25.3(r)-237.2(th)26.5(an)]TJ -17.6189 -1.1116 TD [(th)26.5(at)-297.2(of)-295.9(HA)24.9(dV)25.7(-5)-295.9(\(S)21(c)15(h)0(o)26.6(e)0(h)25.4(n)]TJ /F7 1 Tf 10.6439 0 TD [(e)15(t)-306.5(al)20.7(.)]TJ /F4 1 Tf 2.0159 0 TD [(,)-308.7(2)16.2(00)26.6(8\))20.9(.)-308.7(I)16.2(n)-312.1(a)15(dd)26.6(it)26.3(io)20.7(n)16.2(,)-308.7(CA)24.7(dV)25.7(-2)]TJ -12.6598 -1.1116 TD [(ha)25.4(s)-525(s)16.4(ho)20.8(r)16.2(t)0(e)25.3(r)-525.2(p)16.2(r)0(o)26.6(t)0(u)20.7(b)16.2(er)25.5(an)25.4(ce)18.5(s)-519.3(o)0(n)-509.1(t)0(h)26.5(e)-526.4(t)16.1(o)0(p)-509.1(o)0(f)-509(t)0(h)26.5(e)-526.4(p)16.2(e)0(n)25.4(t)0(o)26.5(n)-525.2(b)16.2(a)0(s)19.9(e)15(,)]TJ 0 -1.1174 TD [(m)15(a)0(i)19.5(n)16.2(ly)-503.4(wh)25.7(er)25.5(e)-520.6(R)15.2(GD)-505(mo)25.4(ti)26.3(f)-519.4(i)16.1(s)-519.3(c)15(on)26.6(ta)19.6(i)16.1(n)0(e)25.4(d)-519.5(i)16.1(n)-519.5(H)15.3(A)0(d)25.7(V)0(s)25.9(,)-516(an)25.4(d)-519.5(a)]TJ 0 -1.1116 TD [(sh)26.8(or)20.9(t)16.1(e)0(r)-498.7(N)0(-)25.8(t)0(e)25.3(r)0(m)25.4(i)0(n)20.7(a)15(l)-513.8(r)16.2(eg)25.4(io)26.5(n.)-499.9(Th)25.4(e)-514.9(h)16.2(yp)26.6(er)25.5(va)25.4(ri)20.7(a)15(b)0(l)26.5(e)-514.9(l)16.1(o)0(o)26.6(p)0(s)-503.1(i)16.1(n)-513.7(t)16.1(he)]TJ T* [(he)25.4(xo)26.6(n)-542.5(p)0(r)20.9(o)16.2(te)25.3(in)-532.2(a)15(r)0(e)-533.2(s)0(h)26.8(o)0(r)26.6(t)0(e)19.6(r)-542.5(i)16.1(n)-542.5(CA)24.7(dV)20(-)16.2(2)-542.5(an)25.4(d)-542.5(t)0(h)26.5(e)-543.7(pr)20.9(o)16.2(t)0(r)26.5(u)0(d)20.8(i)16.1(ng)]TJ 0 -1.1174 TD [(st)26.7(ru)20.9(c)15(t)0(u)26.5(r)0(e)25.5(s)-467.4(co)25.4(nt)20.7(a)15(i)0(n)26.5(i)0(n)26.5(g)-467.6(th)26.5(e)-468.8(e)0(p)25.4(i)0(t)26.3(o)0(p)20.8(e)15(s)-467.4(r)0(e)25.5(c)0(o)25.4(g)0(n)26.6(i)0(z)19.6(e)15(d)-467.6(b)16.2(y)-467.6(a)0(n)25.4(t)0(i)20.6(h)16.2(ex)25.4(on)]TJ 0 -1.1116 TD [(HA)24.9(dV)25.7(-5)-324.7(an)19.7(t)16.1(i)0(b)26.5(o)0(d)26.6(i)0(e)19.6(s)-335(ar)25.5(e)-342.1(a)15(bs)21(e)15(n)0(t)26.5(,)-337.5(wh)25.7(il)20.6(e)-336.3(t)0(h)26.5(e)-342.1()16.3(b)0(e)25.4(r)-340.9(is)-324.7(mo)25.4(re)-325.9(co)25.4(m-)]TJ T* [(pl)26.5(ex)-222.2(si)26.7(nc)25.4(e)-238.4(t)16.1(he)-222.2(sh)26.8(af)19.7(t)-231.6(r)0(e)25.5(g)0(i)26.5(o)0(n)-221.1(c)0(o)25.4(n)0(t)26.5(a)0(i)19.5(n)16.2(s)-237(t)16.1(wo)-221.9(be)25.4(nd)26.6(s)-237(\()16.2(Sc)25.6(ho)20.8(e)15(h)0(n)]TJ /F7 1 Tf 22.1 0 TD [(et)-222.4(a)16.2(l)0(.)]TJ /F4 1 Tf 1.941 0 TD (,)Tj -24.041 -1.1174 TD [(20)26.6(08)26.6(\).)-545.9(A)15.3(l)0(s)20.9(o)16.2(,)-556.4(p)0(r)26.6(o)0(t)20.7(e)15(in)-543.7(IX)-544.4(an)25.4(d)-554(I)0(I)20.9(I)16.2(a)-560.9(a)15(re)-544.7(sh)26.8(or)20.9(t)16.1(e)0(r)-544.7(i)0(n)-543.7(C)15.2(Ad)20(V)15.3(-)0(2)]TJ 0 -1.1116 TD [(\(S)26.8(ch)25.4(oe)19.7(h)16.2(n)]TJ /F7 1 Tf 3.9684 0 TD [(et)-268.4(al)26.5(.)]TJ /F4 1 Tf 1.9871 0 TD 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[(and)-286.7(Tikoo,)-286.7(2004;)-282.1(Bangari)]TJ /F7 1 Tf 10.6958 0 TD [(et)-285.7(al.)]TJ /F4 1 Tf 2.0447 0 TD [(,)-279.9(2005b\).)-286.5(To)-285.6(circumvent)-286.7(this)]TJ -12.7405 -1.1116 TD [(problem,)-439.9(capsid)-435.1(proteins)-436.2(\(ber)-438.4(and)-436.4(pIX\))-431.4(were)-439.5(genetically)]TJ 0 -1.1174 TD [(modied)-499.7(to)-491.9(increase)-502.9(the)-494.2(ability)-499(of)-491.7(BAdV-3)-498.9(to)-491.9(transduce)]TJ 0 -1.1116 TD [(nonbovine)-541.1(cells)-543.5(\(Zakhartchouk)]TJ /F7 1 Tf 13.5987 0 TD [(et)-539.1(al.)]TJ /F4 1 Tf 2.2981 0 TD [(,)-539.1(2007\).)-538.8(Studies)-538.7(on)]TJ -15.8968 -1.1116 TD [(BAdV-3)-412.5(vectors)]TJ /F7 1 Tf 7.1478 0 TD [(in)-399.7(vivo)]TJ /F4 1 Tf 3.2658 0 TD [(biodistribution)-408.7(in)-405.5(a)-405.4(mouse)-405.1(model)]TJ -10.4135 -1.1174 TD [(showed)-313.7(efcient)-311.9(transduction)-309.5(of)-307.4(the)-304.1(heart,)-310.9(kidney,)-310.8(and)-309.7(lung)]TJ 0 -1.1116 TD [(in)-399.7(addition)-402(to)-399.7(liver)-404.3(and)-401.9(spleen)-400.5(with)-403(a)-399.7(longer)-399.5(duration)-401.9(and)]TJ T* [(higher)-336.2(levels)-331.5(of)-330.5(transgene)-335.8(expression)-329.8(than)-334(HAdV-5)-331.7(vectors)]TJ 0 -1.1174 TD (\(Sharma)Tj /F7 1 Tf 3.7323 0 TD [(et)-337.6(al.)]TJ /F4 1 Tf 2.0965 0 TD [(,)-331.7(2009a\).)-339.5(In)-330.5(a)-336.3(mouse)-336(model)-336.3(of)-336.2(breast)-337.1(cancer,)]TJ -5.8288 -1.1116 TD [(the)-482.6(biodistribution)-483.6(of)-474.5(BAdV-3)-481.7(vecto)-8(r)-479.1(was)-477.4(comparable)-483.5(to)]TJ T* [(that)-391.7(of)-388.1(HAdV-5)-389.3(vectors,)-387.8(the)-390.5(vector)-389.2(had)-390.4(the)-390.5(ability)-389.5(to)-382.5(ef-)]TJ 0 -1.1174 TD [(ciently)-275.4(transduce)-272.5(tumor)-271.8(and)-275.2(systemic)-271.4(tissues)-273.5(in)-273(the)-269.5(presence)]TJ 0 -1.1116 TD [(of)-670.3(HAdV-5)-665.8(immunity,)-671.7(and)-666.8(it)-664.8(evaded)-672.5(sequestration)-668.6(by)]TJ T* [(Kupffer)-280.4(cells)-278.6(\(Tandon)]TJ /F7 1 Tf 9.2386 0 TD [(et)-274.2(al.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-279.9(2012\).)-273.9(Also,)-279.4(it)-273.2(has)-280.7(been)-277.4(shown)]TJ -11.2717 -1.1116 TD [(that)-564.5(there)-566.6(is)-560.8(minimal)-564.7(cross-neutralization)-569.4(by)-566.6(preexisting)]TJ 0 -1.1174 TD [(anti-HAdV)-492(immunity)-484(in)-480.4(humans)-486.9(\(Bangari)]TJ /F7 1 Tf 18.2352 0 TD [(et)-481.5(al.)]TJ /F4 1 Tf 2.2405 0 TD [(,)-481.5(2005b\).)]TJ -20.4758 -1.1116 TD [(These)-389(results)-394.6(show)-385.2(the)-384.7(suitability)-394(of)-382.3(BAdV-3)-389.5(vectors)-390.1(as)-389.1(a)]TJ T* [(delivery)-351.2(system)-354.3(for)-348.8(cancer)-351(gene)-346.6(therapy)-350(while)-353.4(circumvent-)]TJ 0 -1.1174 TD [(ing)-550.6(preexisting)-550.3(antivector)-550.5(immunity.)-550.8(Moreover,)-551.1(BAdV-3)]TJ 0 -1.1116 TD [(and)-275.2(HAdV-5)-274.1(vectors)-269.1(have)-277.4(a)-267.2(comparable)-276.2(biological)-273(behavior)]TJ T* [(in)-405.5(human,)-408.8(bovine,)-403(porcine,)-411(and)-407.6(mouse)-405.1(cell)-404.4(lines)-409.9(and)-407.6(both)]TJ 0 -1.1174 TD [(genomes)-247.2(persist)-244.9(at)-245.4(high)-240.7(levels)-245.1(in)-238.5(vector-permissive)-249.1(cell)-248.9(lines)]TJ 0 -1.1116 TD [(in)-394(the)-390.5(absence)-392.3(of)-388.1(immune)-390.5(pressure,)-394.3(proving)-388(BAdV-3)-395.3(vec-)]TJ T* [(tors)-339.4(safety)-337.1(for)-331.5(their)-341(use)-332.6(as)-337.2(gene)-335(delivery)-339.7(vehicles)-334.9(\(Sharma)]TJ /F7 1 Tf T* [(et)-337.6(al.)]TJ /F4 1 Tf 2.0965 0 TD [(,)-331.7(2011\).)]TJ /F10 1 Tf 8.9663 0 0 8.9663 59.7543 292.2519 Tm [(Porcine)-338.6(AdV)-335.3(vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 275.8109 Tm [(Th)19.6(e)-388.2(i)0(d)20.7(e)15(a)-388.2(o)0(f)-376.5(u)0(s)21(i)0(n)20.7(g)-387(PA)20.1(dV)-371.7(\(g)20.9(en)19.7(us)]TJ /F7 1 Tf 13.518 0 TD [(Ma)19.8(st)20.9(ad)20.8(e)15(n)0(o)20.8(v)0(i)19.5(r)0(u)21(s)]TJ /F4 1 Tf 6.2954 0 TD .3836 Tc [(,s)383.6(p)404.6(e)383.6(c)402.1(i)383.6(e)403.1(s)]TJ -20.8271 -1.1116 TD 0 Tc [(Po)21(rc)19.7(in)20.7(e)-405.4(A)0(,)-391.3(B)0(,)-397.2(C)15.2(\))-404.2(v)0(e)19.7(c)0(t)19.5(o)0(r)20.9(s)-404.1(wa)18.8(s)-404.1(p)0(u)20.8(b)16.2(li)20.6(sh)21(ed)-395(ov)20.8(er)-395(20)-393.9(ye)25.4(ar)19.7(s)-404.1(a)0(g)19.7(o)]TJ T* [(\(T)19.7(ub)20.8(ol)20.7(y)]TJ /F7 1 Tf 3.4213 0 TD [(et)-245.4(al)20.7(.)]TJ /F4 1 Tf 1.9698 0 TD [(,)-256.9(1)0(9)20.8(9)0(3)20.8(\))0(.)-246.4(A)-255.4(fe)19.7(w)-255.4(y)0(e)19.7(a)0(r)19.7(s)-254.3(la)19.6(te)25.3(r)-260.2(i)0(t)-244.4(w)0(a)18.8(s)-254.3(di)20.7(sc)19.9(ov)26.6(er)19.7(ed)-245.3(th)20.7(at)]TJ -5.3911 -1.1174 TD [(th)20.7(e)-376.6(v)0(i)20.7(r)0(u)20.9(s)-375.3(ca)18.5(n)-375.5(e)0(n)19.7(t)0(e)19.5(r)-375.4(bu)26.6(t)-381.4(i)16.1(s)-381(u)0(n)26.6(a)0(b)19.7(l)0(e)-366.3(t)0(o)-365.2(r)0(e)19.7(p)0(l)20.7(i)0(c)19.6(a)0(t)25.3(e)-376.6(in)-365.2(do)20.8(g,)-367.4(sh)21(ee)18.5(p)16.2(,)]TJ 0 -1.1116 TD [(bo)20.8(vi)20.7(ne)19.7(,)-395.1(a)0(n)19.7(d)-398.5(hu)20.8(ma)18.4(n)-392.8(c)0(e)18.5(l)0(l)20.6(s)-398.3(\(R)19.8(ed)19.7(dy)]TJ /F7 1 Tf 13.7081 0 TD [(et)-389.4(al)20.7(.)]TJ /F4 1 Tf 2.1196 0 TD [(,)-395.1(1)0(9)20.8(9)0(9)20.8(a)0(\))19.7(.)-395.1(So)21(on)-388.1(af)19.7(te)19.6(r)16.2(,)]TJ -15.8277 -1.1116 TD [(PA)20.1(dV)20(-3)-261.3(\(P)21(A)15.3(d)0(V)-262.3(A)-266.9(sp)21(ec)18.5(ie)19.6(s\))-261.2(ve)25.4(ct)19.6(or)20.9(s)-271.6(w)0(e)18.8(r)0(e)-256.8(c)0(o)19.7(n)0(s)21(t)0(r)20.7(u)0(c)19.7(t)16.1(ed)-262.5(wi)19.8(th)-255.8(th)20.7(e)]TJ 0 -1.1174 TD [(lo)20.7(ng)20.8(-t)20.7(er)19.7(m)-209.7(o)0(b)20.8(j)0(e)19.5(c)0(t)19.5(i)0(v)20.7(e)-215.4(t)16.1(o)-214.2(de)19.7(ve)19.7(lo)20.7(p)-208.4(r)0(e)19.7(p)0(l)20.7(i)0(c)19.6(a)0(t)19.5(i)0(o)20.7(n)0(-)20.9(c)15(om)19.6(pe)19.7(te)19.6(nt)-198.2(PA)20.1(dV)20(-3)]TJ 0 -1.1116 TD [(as)-383.3(a)-388.2(l)0(i)20.6(v)0(e)-377.7(g)0(e)25.4(n)0(e)-383.5(t)0(r)26.5(a)0(n)19.7(s)0(f)21.1(e)0(r)-377.7(v)0(e)19.7(c)0(t)19.5(o)0(r)-376.5(t)0(o)-376.7(i)0(n)20.7(d)0(u)20.8(c)0(e)-378.9(a)-388.2(mu)19.6(co)19.7(sa)19.9(l)-387.1(i)0(m)19.5(m)15(un)20.8(e)]TJ T* [(re)19.7(sp)21(on)20.8(se)-250.8(in)-244.2(pi)20.7(gs)-249.7(\(R)19.8(ed)19.7(dy)]TJ /F7 1 Tf 9.7569 0 TD [(et)-251.2(al)20.7(.)]TJ /F4 1 Tf 1.9756 0 TD [(,)-262.6(1)0(9)20.8(9)0(9)20.8(b)16.2(\).)-252.2(Re)18.6(c)15(o)0(m)19.6(b)0(i)20.7(n)0(a)19.7(n)0(t)-244.2(P)0(A)20.1(d)0(V)20(-)0(3)]TJ -11.7325 -1.1116 TD [(is)-163.4(an)-164.6(ef)19.7(fe)19.7(ct)19.5(iv)20.7(e)-169.3(d)0(e)19.7(l)0(i)20.6(v)0(e)19.7(r)0(y)-163.4(s)0(y)21(s)0(t)20.9(e)0(m)-160.1(i)0(n)-163.6(p)0(i)20.7(g)0(s)-163.3(\()0(H)20(a)0(m)18.5(m)15(on)20.8(d)-173.9(a)0(n)19.7(d)-173.9(Jo)21(hn)20.8(so)21(n,)]TJ 0 -1.1174 TD [(20)20.8(05)20.8(\),)-309.8(an)25.4(d)-323.6(i)16.1(t)-323.8(i)16.1(s)-323.4(o)0(f)20.9(t)16.1(en)-308.6(st)20.9(ud)20.8(ie)19.6(d)-317.9(t)0(o)20.7(g)0(e)19.7(t)0(h)20.7(e)15(r)-323.6(w)15.3(it)20.6(h)-317.9(B)0(A)18.9(d)0(V)20(-)0(3)-307.4(v)0(e)19.7(c)0(t)19.6(o)16.2(rs)21.1(,)]TJ 0 -1.1116 TD [(sh)21(ow)20(in)20.7(g)-778.7(s)0(i)20.9(m)15(il)20.6(ar)-769.4(pr)20.9(op)20.8(er)19.7(ti)26.3(es)19.9(:)-778.8(l)0(a)19.6(c)0(k)-769.4(o)0(f)-762.4(c)0(r)19.7(o)0(s)21(s)0(-)21.1(n)0(e)19.7(u)0(t)20.7(r)0(a)19.7(l)0(i)20.6(z)15(at)19.6(io)20.7(n)]TJ T* [(wi)19.8(th)-169.4(pr)20.9(ee)18.5(xi)20.7(st)20.9(in)20.7(g)-179.6(a)15(nt)20.7(i-)20.7(HA)19.1(dV)-170.1(im)19.5(m)15(u)0(n)20.8(i)0(t)20.6(y)-179.6(in)-169.4(hu)20.8(ma)18.4(ns)-169(\(B)19.8(an)25.4(ga)19.7(ri)-169.3(an)19.7(d)]TJ 0 -1.1174 TD [(Mi)19.8(tt)20.6(al)19.5(,)-521.8(2)0(0)26.6(0)0(4)20.8(;)-525.4(B)15.2(a)0(n)19.7(g)0(a)19.7(r)0(i)]TJ /F7 1 Tf 9.5554 0 TD [(et)-510.3(al)20.7(.)]TJ /F4 1 Tf 2.2405 0 TD -.0206 Tc [(,)-536.6(2)-20.6(00)-20.6(5b)-20.6(\),)-542.4(C)-20.6(A)4.1(R)-20.6(-)-536.4(a)-5.6(n)-20.6(d)-535.4(i)-20.6(n)5.9(t)-20.6(eg)-20.6(ri)-20.6(n-)]TJ -11.7959 -1.1116 TD 0 Tc [(in)20.7(de)19.7(pe)19.7(nd)20.8(en)25.4(t)-462(c)15(el)19.5(l)-456.2(e)0(n)19.7(t)0(r)20.7(y)-456.1(\(B)19.8(an)19.7(ga)19.7(ri)-445.8(an)19.7(d)-456.1(M)15.3(it)20.6(ta)19.6(l,)-448.2(20)20.8(05)26.6(;)-462(B)15.2(an)19.7(ga)19.7(ri)]TJ /F7 1 Tf T* [(et)-291.5(al)20.7(.)]TJ /F4 1 Tf 2.0217 0 TD [(,)-297.2(2)0(0)20.8(0)0(5)20.8(b)0(\))20.9(,)-302.9(si)20.9(m)15(i)0(l)20.6(a)0(r)-291.3(s)0(a)19.9(f)0(e)19.7(t)0(y)-290.3(p)0(r)20.9(o)0()21(l)0(e)-291.5(a)0(n)25.4(d)-306.4(b)16.2(i)0(o)20.7(l)0(o)20.7(g)0(i)20.7(c)0(a)18.5(l)-300.7(ch)19.7(ar)25.5(ac)18.5(te)19.6(r-)]TJ -2.0217 -1.1174 TD [(is)20.9(ti)20.6(cs)-343(\(S)21(ha)19.7(rm)25.4(a)]TJ /F7 1 Tf 6.0419 0 TD [(et)-337.6(al)20.7(.)]TJ /F4 1 Tf 2.0677 0 TD -.0203 Tc [(,)-369.3(2)-20.3(01)-20.3(1\))-20.3(,)-358.9(e)-20.3(f)-20.3(ci)-20.3(e)5(n)-20.3(t)-362.4(t)-20.3(ra)-20.3(ns)-20.3(du)-20.3(c)5.1(t)-20.3(io)-20.3(n)-362.3(o)-20.3(f)-362.3(s)-20.3(e)5.3(v)-20.3(er)-20.3(al)]TJ -8.1097 -1.1116 TD 0 Tc [(ce)18.5(ll)-175.2(ty)26.5(pe)19.7(s)-185.2(o)0(f)-169.2(v)0(a)19.7(r)0(i)20.7(o)0(u)20.8(s)-185.2(sp)21(e)15(c)0(i)19.5(e)0(s)-176(w)0(i)19.8(t)0(h)-169.4(P)0(A)20.1(d)0(V)20(-)0(3)-169.2(h)0(a)19.7(v)0(i)20.7(n)0(g)-169.2(a)0(n)-176.1(a)0(d)19.7(v)0(a)19.7(n)16.2(ta)19.6(ge)]TJ T* [(in)-192.4(sp)21(ec)18.5(i)20.9(c)-203.8(t)0(a)19.5(r)16.2(ge)19.7(ti)20.6(ng)-192.3(of)-192.2(th)20.7(e)-203.8(b)0(r)20.9(e)15(as)19.9(t)-202.8(t)0(i)20.6(s)0(s)21.2(u)0(e)-193.4(\()0(B)19.8(a)0(n)19.7(g)16.2(ar)19.7(i)]TJ /F7 1 Tf 18.9034 0 TD [(et)-193.6(al)20.7(.)]TJ /F4 1 Tf 1.918 0 TD -.0208 Tc [(,)-225.8(2)-20.8(00)-20.8(5b)-20.8(\),)]TJ -20.8213 -1.1174 TD 0 Tc [(an)19.7(d)-364(t)0(h)20.7(e)-370.9(v)16.2(e)0(c)18.5(t)0(o)20.7(r)-363.9(ge)19.7(no)20.8(me)18.4(s)-363.8(r)0(e)19.7(m)0(a)18.4(i)0(n)-353.7(a)0(s)-354.5(l)0(i)20.6(n)0(e)19.7(a)0(r)-354.7(e)0(p)19.7(i)0(s)20.9(o)0(m)25.4(e)0(s)-360.3(\()0(S)21(h)16.2(ar)19.7(ma)]TJ /F7 1 Tf 0 -1.1116 TD [(et)-314.5(al)20.7(.)]TJ /F4 1 Tf 2.0389 0 TD [(,)-326(2)0(0)20.8(0)0(9)20.8(a)15(\).)-315.5(In)-313.2(co)25.4(nt)20.7(ra)19.7(st)-313.2(wi)19.8(th)-313.4(BA)24.7(dV)20(-3)-313.2(ve)19.7(ct)19.5(or)20.9(s,)-309.6(th)20.7(e)-324.8(g)0(e)25.4(n)0(o)20.8(m)0(e)]TJ 23.4708 67.9184 TD [(le)19.6(ve)25.4(ls)-422.6(of)-416.9(PA)20.1(dV)20(-3)-416.9(ve)19.7(ct)19.5(o)16.2(r)-433(we)18.8(re)-418(sh)21(ow)20(n)-427.3(t)0(o)-417(b)0(e)-418.1(c)0(o)19.7(m)0(p)19.6(a)0(r)25.5(a)0(b)19.7(l)0(e)-418.2(o)0(r)]TJ 0 -1.1174 TD [(lo)20.7(we)24.6(r)-208.4(t)0(h)20.7(a)0(n)-199.2(t)0(h)20.7(o)0(s)21(e)-209.6(of)-198(HA)24.9(dV)20(-5)-198(ve)19.7(ct)19.5(or)20.9(s)]TJ /F7 1 Tf 14.3417 0 TD [(in)-198.2(v)15(i)0(v)19.5(o)]TJ /F4 1 Tf 2.828 0 TD [(in)-198.2(a)-209.6(m)0(o)19.6(u)0(s)21(e)-203.9(mo)19.6(de)19.7(l,)]TJ -17.1697 -1.1116 TD [(ex)19.7(c)15(e)0(p)19.7(t)-277.7(in)-267.3(th)20.7(e)-273(c)0(a)18.5(s)0(e)-268.1(o)0(f)-267.1(t)0(h)26.5(e)-278.7(he)19.7(ar)19.7(t,)-263.8(wh)20(er)19.7(e)-278.7(t)16.1(he)-268.3(le)19.6(ve)19.7(ls)-267.1(w)15.3(e)0(r)19.7(e)-278.7(co)19.7(mp)19.6(a)15(-)]TJ T* [(ra)19.7(bl)26.5(e)-192.3(o)0(r)-175(h)0(i)20.7(g)0(h)20.8(e)0(r)-181.9(\()0(S)21(h)16.2(ar)19.7(ma)]TJ /F7 1 Tf 9.3826 0 TD [(e)15(t)-191.3(al)20.7(.)]TJ /F4 1 Tf 1.9007 0 TD -.0202 Tc [(,)-207.9(2)-20.2(00)-20.2(9a)-20.2(\).)-207.9(T)-20.2(h)-.6(e)-206.8(s)-20.2(pe)-20.2(ci)-20.2(c)-20.2(it)-20.2(y)-195.3(o)-20.2(f)-200.9(P)-20.2(Ad)-20.2(V)]TJ -11.2833 -1.1116 TD 0 Tc [(ve)19.7(c)15(t)0(o)20.7(r)0(s)-249.6(f)0(o)20.9(r)-254.5(di)20.7(st)20.9(in)20.7(ct)-245.4(ti)20.6(ss)21.2(ue)19.7(s)-254.3(i)0(s)-244(v)0(e)19.7(r)0(y)-244.1(i)0(n)20.7(t)0(e)19.6(r)0(e)19.7(s)0(t)20.9(i)0(n)20.7(g)-254.5(fo)20.9(r)-254.5(t)0(h)20.7(e)-255.7(de)19.7(si)20.9(gn)-244.1(of)]TJ 0 -1.1174 TD [(ve)19.7(c)15(t)0(o)20.7(r)0(s)-261.2(f)0(o)20.9(r)-266(ta)19.6(rg)20.9(et)19.5(ed)-256.8(ge)19.7(ne)-262.5(d)16.2(e)0(l)19.5(i)0(v)20.7(e)0(r)19.7(y)0(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 642.9542 Tm [(Simian)-331.1(AdV)-335.3(vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 320.8251 626.5132 Tm [(Si)20.9(mi)19.5(an)-527.5(Ad)20(Vs)-527(ar)19.7(e)-537.9(g)0(r)20.9(o)0(u)20.8(p)0(e)19.7(d)-536.7(in)20.7(to)-526.5(se)14.1(ve)19.7(ra)19.7(l)-536.9(h)0(u)20.8(m)0(a)18.4(n)-536.7(\(c)19.7(er)19.7(ta)19.6(in)]TJ -1.0137 -1.1116 TD [(HA)19.1(dV)-233.5(sp)21(ec)18.5(ie)19.6(s)-242.8(c)0(o)19.7(n)0(t)14.9(a)0(i)19.5(n)-243(si)20.9(mi)19.5(an)-233.7(or)-232.6(ap)19.7(e)-244.2(A)0(d)20(V)0(s)20.2(,)-245.3(ba)19.7(se)19.9(d)-243(o)0(n)-232.6(s)0(p)21(e)0(c)18.5(i)0(e)19.5(s)0(-)]TJ 0 -1.1174 TD [(de)19.7(ma)18.4(rc)19.7(at)19.5(io)20.7(n)-427.3(c)0(r)19.7(i)0(t)20.6(e)0(r)19.7(i)0(a)-418.2(s)0(u)21(c)0(h)-418.1(a)0(s)-412.1(p)0(h)20.8(y)0(l)14.9(o)0(g)20.8(e)0(n)19.7(e)0(t)19.5(i)0(c)-418.2(d)0(i)20.7(s)0(t)20.9(a)0(n)19.7(c)0(e)-419.2(a)0(n)19.7(d)-421.6(nu)20.8(-)]TJ 0 -1.1116 TD [(cl)19.5(eo)19.7(ti)20.6(de)-487.2(co)19.7(mp)19.6(os)21(it)14.8(io)20.7(n\))-486(an)19.7(d)-490.7(s)0(i)15.1(m)15(ia)13.8(n)-490.7(A)0(d)20(V)-497.3(sp)21(ec)18.5(ie)13.8(s)-490.5(w)0(i)19.8(t)0(h)15(i)0(n)-480.4(t)0(h)20.7(e)]TJ T* [(ge)19.7(nu)20.8(s)]TJ /F7 1 Tf 2.5919 0 TD [(Ma)19.8(st)15.1(ad)20.8(en)19.7(ov)19.7(ir)20.9(us)]TJ /F4 1 Tf 6.3126 0 TD [(.)-297.2(T)0(h)19.6(e)-301.8(r)21(st)-295.9(ge)19.7(ne)-291.4(tr)20.7(an)19.7(sf)21.1(er)-297.1(ve)19.7(ct)19.5(or)-290.2(de)19.7(ri)20.7(ve)19.7(d)]TJ -8.9045 -1.1116 TD [(fr)20.9(om)-1103.5(ch)13.9(im)19.5(pa)19.7(nz)19.7(ee)-1104.6(Ad)14.2(V-)20(68)-1102.3(\(C)19.8(hA)14.2(dV)20(-6)20.9(8/)20.7(Pa)19.8(n)-1118.5(9)0(/)20.7(S)0(A)20.1(d)0(V)20(-)]TJ 0 -1.1174 TD [(25)20.8(;)-675.1(s)0(p)21(e)0(c)18.5(i)0(e)19.6(s)-674.8(HA)19.1(dV)-665.4(E\))-665.7(wa)18.8(s)-674.8(a)0(b)19.7(l)0(e)-660.1(t)0(o)-664.7(g)0(r)20.9(o)0(w)-665.4(i)0(n)-664.7(H)0(E)18.8(K)0(2)20(9)0(3)20.8(-)]TJ 0 -1.1116 TD [(co)19.7(mp)19.6(le)19.5(me)18.5(nt)20.7(in)20.7(g)-294.8(c)0(e)12.8(l)0(l)20.6(s)-294.6(wi)19.8(th)20.7(ou)20.8(t)-295(b)0(e)13.9(i)0(n)20.7(g)-294.8(ne)19.7(ut)20.7(ra)19.7(li)20.6(ze)12.8(d)-294.8(b)0(y)-284.4(a)0(n)19.7(t)0(i)20.6(b)0(o)20.8(d)0(i)20.7(e)0(s)]TJ T* [(ag)19.7(ai)19.5(ns)21(t)-323.8(H)0(A)13.3(d)0(V)-314.1(s)0(e)19.9(r)0(o)20.9(t)0(y)20.7(p)0(e)13.9(s)-323.4(\(F)21(ar)19.7(in)20.7(a)]TJ /F7 1 Tf 13.2416 0 TD [(et)-320.3(al)20.7(.)]TJ /F4 1 Tf 2.0447 0 TD [(,)-326(2)0(0)20.8(0)0(1)15.1(\))0(.)-309.8(S)0(i)15.1(n)0(c)19.7(e)-324.8(ne)19.7(ut)20.7(ra)19.7(l-)]TJ -15.2863 -1.1174 TD [(iz)19.6(in)20.7(g)-277.6(s)0(e)19.9(r)0(o)15.1(p)0(r)20.9(e)0(v)19.7(a)0(l)19.5(e)0(n)19.7(c)0(e)-269.5(t)0(o)-267.3(C)0(h)19.8(A)0(d)20(V)0(-)14.2(6)0(8)-267.1(i)0(n)-267.3(d)0(i)20.7(f)0(f)20.9(e)0(r)19.7(e)0(n)13.9(t)-277.7(re)19.7(gi)20.7(on)20.8(s)-277.4(o)0(f)-267.1(t)0(h)14.9(e)]TJ 0 -1.1116 TD [(wo)20(rl)20.7(d)-519.5(i)0(s)-503.2(s)0(i)20.9(g)0(n)15.1(i)0()20.9(c)0(a)18.5(n)0(t)20.7(l)0(y)-509.2(l)0(o)20.7(w)0(e)18.8(r)-513.7(th)15(an)-504.5(th)20.7(at)-510.3(to)-503.4(HA)19.1(dV)20(-5)-509(\(X)20(ia)19.5(ng)]TJ /F7 1 Tf T* [(et)-303(al)20.7(.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-308.7(2)0(0)20.8(0)0(6)20.8(;)-312.3(Er)13.9(sc)19.9(hi)20.7(ng)]TJ /F7 1 Tf 6.9174 0 TD [(et)-303(al)20.7(.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-308.7(2)0(0)15.1(1)0(0)20.8(;)-312.2(Zh)19.6(an)19.7(g)]TJ /F7 1 Tf 5.9498 0 TD [(et)-303(al)20.7(.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-308.7(2)0(0)20.8(1)0(3)15.1(a)0(\))19.7(,)-308.7(th)20.7(at)]TJ -18.9667 -1.1174 TD [(ma)18.4(ke)19.7(s)-363.8(i)0(t)-348(a)-365.1(go)20.8(od)-347.8(ca)12.8(nd)20.8(id)20.7(at)19.5(e)-365.1(f)0(o)20.9(r)-358.2(ap)19.7(pl)14.9(ic)19.6(at)19.5(io)20.7(n)-364(i)0(n)-347.9(h)0(u)20.8(m)0(a)18.5(n)0(s)15.3(.)-360.5(In)20.9(te)19.5(r-)]TJ 0 -1.1116 TD [(es)19.9(ti)20.6(ng)20.8(ly)15(,)-326(a)-330.6(si)20.9(ng)20.8(le)-320.3(su)21(rf)15.1(ac)18.5(e)-324.8(l)0(o)15(o)0(p)-313.2(d)0(e)13.9()0(n)21(e)0(s)-320(a)-324.8(ma)18.4(jo)14.9(r)-323.6(n)0(e)19.7(u)0(t)14.9(r)0(a)19.7(l)0(i)20.6(z)0(a)18.5(t)0(i)20.6(o)0(n)]TJ T* [(si)20.9(te)-423.9(fo)20.9(r)-433(t)0(h)20.7(e)-434.2(Ch)19.8(Ad)14.2(V-)20(68)-422.7(he)19.7(xo)20.8(n)-433.1(\()0(P)21(i)0(c)19.5(h)0(l)14.9(a)0(-)19.7(G)0(o)20(l)0(l)20.6(o)0(n)]TJ /F7 1 Tf 18.9206 0 TD [(et)-424(al)20.7(.)]TJ /F4 1 Tf 2.1541 0 TD .4296 Tc [(,2)429.6(0)444.7(0)429.6(7)450.4(\))429.6(,)]TJ -21.0748 -1.1174 TD 0 Tc [(wh)20(ic)19.6(h)-507.9(w)0(h)20(e)0(n)-498.7(m)0(u)19.6(t)0(a)13.8(t)0(e)19.6(d)0(,)-494.1(p)0(e)13.9(r)0(m)19.6(i)0(t)20.6(t)0(e)19.6(d)-507.9(th)20.7(e)-509.1(v)0(i)20.7(r)0(u)15.1(s)-507.8(to)-497.7(es)19.9(ca)18.5(pe)-498.7(fr)15.2(om)]TJ 0 -1.1116 TD [(ne)19.7(ut)20.7(ra)19.7(li)14.8(za)18.5(ti)20.6(on)-376.6(by)-376.6(po)20.8(ly)20.7(cl)19.5(on)15.1(al)-377.9(an)19.7(ti)20.6(se)19.9(ra)-377.7(ob)20.8(ta)13.8(in)20.7(ed)-377.7(fr)20.9(om)-377.8(an)19.7(im)19.5(al)19.5(s)]TJ /F7 1 Tf T* [(in)-267.3(vi)19.5(tr)15.1(o)]TJ /F4 1 Tf 2.8971 0 TD [(.)-279.9(T)0(h)19.6(i)0(s)-272.8(w)0(a)18.8(s)-277.4(ac)18.5(tu)20.7(al)13.8(ly)-267.3(th)20.7(e)-284.5()0(r)21(s)0(t)-272.8(n)0(e)19.7(u)0(t)20.7(r)0(a)19.7(l)0(i)20.6(z)0(i)19.5(n)0(g)-272.9(s)0(i)20.9(t)0(e)-274.2(i)0(d)20.7(e)0(n)19.7(t)0(i)20.6()0(e)19.8(d)]TJ -2.8971 -1.1116 TD [(fo)20.9(r)-427.3(a)0(n)13.9(y)-427.3(Ad)20(V,)-420.1(wh)20(ic)19.6(h)-433.1(w)0(a)18.8(s)-427.1(la)13.8(te)19.6(r)-427.3(v)0(e)19.7(r)0(y)-422.6(i)0(m)19.5(p)0(o)20.8(r)0(t)20.7(a)0(n)19.7(t)-433.2(fo)20.9(r)-433(t)0(h)20.7(e)-428.5(su)21(c-)]TJ 0 -1.1174 TD [(ce)18.5(ss)21.2(fu)20.9(l)-248.9(a)0(p)13.9(p)0(l)20.7(i)0(c)19.6(a)0(t)19.5(i)0(o)20.7(n)-248.8(of)-238.3(th)15(e)-249.9(v)0(e)19.7(c)0(t)19.6(o)0(r)20.9(s)-248.6(in)-238.5(th)15(e)-244.2(c)0(l)13.8(i)0(n)20.7(i)0(c)19.6(s)0(.)-240.5(G)0(e)18.8(n)0(e)-239.5(d)0(e)19.7(l)0(i)20.6(v)0(e)19.7(r)0(y)]TJ 0 -1.1116 TD [(by)-365.1(Ch)19.8(Ad)20(V-)20(68)-365.1(is)-365(CA)18.9(R)-376.5(d)0(e)19.7(p)0(e)19.7(n)0(d)20.8(e)0(n)19.7(t)-375.6(\(C)19.8(oh)15.1(en)]TJ /F7 1 Tf 17.233 0 TD [(et)-366.4(al)20.7(.)]TJ /F4 1 Tf 2.0965 0 TD .372 Tc [(,2)372(0)387.1(0)372(2)392.8(\))372(,)10.4(a)372(n)391.7(d)]TJ -19.3296 -1.1116 TD 0 Tc [(un)20.8(li)20.6(ke)-268.3(th)20.7(e)]TJ /F7 1 Tf 4.2219 0 TD (E1)Tj /F4 1 Tf 1.3766 0 TD [(of)-267.1(HA)19.1(dV)20(-5)15.1(,)-274.1(t)0(h)20.7(e)-278.7(a)19.8(nk)20.8(in)20.7(g)-277.6(s)0(e)19.9(q)0(u)20.8(e)0(n)19.7(c)0(e)18.5(s)-277.4(o)21.9(f)-260.3(C)20.9(h)21.9(A)21.1(d)21.9(V)26.8(-)]TJ -5.5984 -1.1174 TD -.022 Tc [(68)-466.6(are)-467.8(nonh)5.7(omolo)5.7(gous)-466.4(wit)5.6(h)-466.6(cell-)5.7(derived)]TJ /F7 1 Tf 16.8126 0 TD -.0207 Tc (E1)Tj /F4 1 Tf 1.0713 0 TD -.0216 Tc [(,)-462.8(p).3(reven)6.1(ting)-466.2(t).2(h)6.1(e)]TJ -17.8839 -1.1116 TD [(fo)6.2(rmatio)6.2(n)-253(o).4(f)-247.2(r).5(ep)6.2(licat)6.1(ion-com)5(p).4(ete)5(n).4(t)-253.1(v)6.2(iruses)-247(\(Xia)5(ng)]TJ /F7 1 Tf 19.4505 0 TD -.0256 Tc [(et)-257.2(al.)]TJ /F4 1 Tf 1.8949 0 TD -.0219 Tc [(,)-250(2)0(0)5.8(02\).)]TJ -21.3455 -1.1116 TD -.0227 Tc [(Development)-271.6(o)-.8(f)-271.4(v)-.8(ectors)-271.3(derived)-271.5(fro)5(m)-272.7(c)-1.9(himpanzee)-272.6(A)-1.6(dVs)-271.3(P)-.6(an)-271.5(5)]TJ 0 -1.1174 TD -.0221 Tc [(\(ChAdV-5)5.6(/SAdV-2)5.6(2)-.2(\),)-330.8(Pan)-328.5(6)-328.5(\()-.1(ChAdV-6/)5.5(SAdV-2)5.6(3\),)-330.8(a)-1.3(nd)-328.5(Pan)-328.5(7)]TJ 0 -1.1116 TD -.0216 Tc [(\(C)5.1(hAdV-7)6.1(/SAdV-2)6.1(4).3(\),)-290(mem)4.9(b).3(ers)-293.2(o).3(f)-287.6(HAdV)-288.5(E)-294.6(spe)4.9(c)-.8(ies,)-290(sta)4.9(r).4(ted)-293.4(i)6(n)]TJ T* -.0218 Tc [(20)5.9(04)-241.8(\(Roy)]TJ /F7 1 Tf 4.3025 0 TD -.0213 Tc [(et)-241.4(al.)]TJ /F4 1 Tf 1.8892 0 TD -.0218 Tc [(,)-244.1(200)5.9(4\).)-244.1(T)-1.1(h)5.9(e)-248.7(v)5.9(ector)5.9(s)-247.3(t)0(r)5.9(a)-1(nsduced)-241.8(skelet)5.8(al)-241.9(muscle)]TJ -6.1917 -1.1116 TD [(wi)5.7(th)-264.9(th)5.8(e)-266.1(s).2(ame)-266.1(e)4.6(fcien)5.8(cy)-264.9(as)-264.7(HAd)5.8(V-5)-264.9(v)5.8(ectors,)-261.5(b)5.8(u)0(t)-265(w)-.8(i)5.7(t)-.1(hout)-259.3(bein)5.8(g)]TJ 0 -1.1174 TD [(neutrali)5.9(zed)-535.4(by)-529.6(human)-529.6(sera,)-532(a)-.9(nd)-535.4(t)5.9(h).2(e)-536.6(n).2(eu)6(tralization)-535.4(d)6(omain)6(s)]TJ 0 -1.1116 TD -.0222 Tc [(sho)5.5(w)-1.1(ed)-380.4(to)-380.4(b)5.5(e)-381.6(differ)5.5(e)-1.4(nt)-380.5(in)-380.4(Pan)-380.4(6)-380.4(a)-1.4(nd)-380.4(Pan)-380.4(7)-380.4(both)]TJ /F7 1 Tf 19.6118 0 TD -.0226 Tc [(in)-380.8(vitro)]TJ /F4 1 Tf 3.2773 0 TD -.0208 Tc [(an)6.9(d)]TJ /F7 1 Tf -22.8891 -1.1116 TD -.0215 Tc [(in)-327.9(vivo.)]TJ /F4 1 Tf 1.0137 -1.1174 TD 0 Tc [(One)-535.2(study)-535.3(investigated)-535.4(the)-534.5(importance)-540.1(of)-532.1(neutralizing)]TJ -1.0137 -1.1116 TD [(determinants)-392.5(on)-388.1(capsid)-394.8(proteins)-390.2(by)-393.9(using)-385.6(chimeric)-393.9(vectors)]TJ T* [(with)-259(different)-265.8(combinations)-264.6(of)-261.4(Pan)-257.7(7)-260.3(and)-263.6(Pan)-263.5(6)-260.3(penton)-261.3(base,)]TJ 0 -1.1174 TD [(and)-401.9(hexon)-404.1(and)-401.9(ber)-402.8(proteins)-401.7(\(Roy)]TJ /F7 1 Tf 14.814 0 TD [(et)-400.9(al.)]TJ /F4 1 Tf 2.1599 0 TD [(,)-400.8(2005\),)-406.3(reporting)]TJ -16.9739 -1.1116 TD [(that)-380.2(both)-384.7(hexon)-381.1(and)-384.6(ber)-379.8(have)-381.1(neutralization)-389.3(epitopes)-385.6(and)]TJ T* (that)Tj /F7 1 Tf 1.9525 0 TD [(in)-445.8(vivo)]TJ /F4 1 Tf 3.3464 0 TD [(transduction)-447.7(was)-448.6(more)-444.5(affected)-445.5(by)-445.7(antihexon)]TJ -5.2989 -1.1174 TD [(antibodies,)-391.4(with)-397.2(no)-388.1(effect)-396.1(of)-393.8(antipenton)-393.9(base)-392.4(NAbs.)-395.3(Other)]TJ 0 -1.1116 TD [(studies)-481(on)-486(seroprevalence)-488.8(rates)-485.8(of)-480.2(various)-481.1(ChAdVs)-487.3(were)]TJ T* [(carried)-454.8(out,)-450.4(with)-449(Pan)-447.8(6)-450.4(and)-453.7(Pan)-447.8(7)-450.4(seeming)-454.7(promising)-454.7(as)]TJ T* [(ge)19.7(ne)-239.5(th)20.7(er)19.7(ap)19.7(y)-248.8(v)0(e)19.7(c)0(t)19.6(o)0(r)15.1(s)-242.8(al)13.8(th)20.7(ou)20.8(gh)-238.3(de)19.7(pe)19.7(nd)20.8(in)20.7(g)-248.8(o)0(n)-238.3(t)0(h)20.7(e)-249.9(re)19.7(gi)20.7(on)-238.3(wh)20(er)13.9(e)]TJ 0 -1.1174 TD [(th)20.7(e)-503.3(p)0(o)20.8(t)0(e)19.6(n)0(t)20.7(i)0(a)13.8(l)-502.3(pa)19.7(ti)20.6(en)19.7(ts)-491.7(li)14.8(ve)-492.9(\()-116.3(J)0(i)20.9(a)0(n)]TJ /F7 1 Tf 13.7311 0 TD [(et)-493.1(al)20.7(.)]TJ /F4 1 Tf 2.2232 0 TD [(,)-504.5(2)0(0)20.8(1)0(3)20.8(\))0(.)-494.1(A)-503.1(tr)20.7(op)20.8(is)20.9(m-)]TJ -15.9544 -1.1116 TD [(mo)19.6(di)20.7(e)19.8(d)-271.8(d)0(e)19.7(r)0(i)20.7(v)0(a)19.7(t)0(i)20.6(v)0(e)-262.5(o)0(f)-255.6(P)0(a)19.8(n)-271.8(7)-266(s)0(h)15.3(o)0(w)20(e)0(d)-256.8(s)0(e)19.9(v)0(e)19.7(r)0(a)14(l)-266.2(ad)19.7(va)19.7(nt)14.9(ag)19.7(es)-256.6(ov)20.8(er)]TJ T* [(HA)19.1(dV)20(-5)-445.7(fo)20.9(r)-456.1(t)0(h)20.7(e)-451.5(us)15.3(e)-451.5(i)0(n)-445.8(g)0(e)19.7(n)0(e)-441.1(t)0(h)15(e)0(r)19.7(a)0(p)19.7(y)0(:)-445.8(l)0(o)20.7(w)0(e)18.8(r)-456.1(de)19.7(gr)20.9(ee)-442.3(of)-445.7(in)20.7(-)]TJ 0 -1.1174 TD [(ac)18.5(ti)20.6(va)19.7(ti)20.6(on)15.1(,)-608.2(d)0(i)14.9(m)0(i)19.5(n)0(i)20.7(s)0(h)21(e)0(d)-602.4(l)0(i)14.8(v)0(e)19.7(r)-611.6(tr)20.7(an)19.7(sd)15.3(uc)19.7(ti)20.6(on)-601.2(ca)18.5(us)15.3(ed)-602.4(by)-601.2(po)20.8(or)]TJ 0 -1.1116 TD [(st)20.9(ab)19.7(il)20.6(it)14.8(y)-352.4(o)0(f)-347.7(F)0(X)20.1(-)0(P)21(a)0(n)-348.9(7)-352.4(co)13.9(m)15(p)0(l)14.9(e)0(x)19.7(e)0(s)19.9(,)-354.8(gr)20.9(ea)18.5(te)13.8(r)-352.4(g)0(e)19.7(n)0(e)-348.9(d)0(e)19.7(l)0(i)20.6(v)0(e)19.7(r)0(y)-347.7(e)0(f)19.7()0(-)]TJ T* [(ci)19.5(en)19.7(cy)-343.2(th)20.7(an)-343.2(th)20.7(e)-353.6(w)0(i)14.1(l)0(d)20.7(-)0(t)20.7(y)0(p)20.8(e)-353.6(co)19.7(nt)20.7(ro)15.1(l)-352.6(P)0(a)19.8(n)-352.4(7)-352.4(v)0(e)19.7(c)0(t)19.6(o)0(r)]TJ /F7 1 Tf 19.2893 0 TD [(in)-342.2(vi)19.5(tr)15.1(o)]TJ /F4 1 Tf 2.972 0 TD .349 Tc [(,a)349(n)368.7(d)]TJ -22.2613 -1.1174 TD 0 Tc [(hi)20.7(gh)20.8(er)-435.3(tr)20.7(an)13.9(sd)21(uc)19.7(ti)20.6(on)]TJ /F7 1 Tf 8.2479 0 TD [(in)-434.3(vi)19.5(vo)]TJ /F4 1 Tf 3.3061 0 TD [(of)-434.1(th)15(e)-445.8(H)0(e)18.8(r)0(2)-434.1(\()0(h)20.9(u)0(m)19.6(a)0(n)-435.3(e)0(p)19.7(i)0(d)20.7(e)0(r)19.7(m)0(a)18.4(l)]TJ -11.554 -1.1116 TD [(gr)20.9(ow)20(th)-296.1(fa)19.7(ct)19.5(or)-290.1(re)19.7(ce)12.8(pt)20.7(or)-290.1(ty)20.7(pe)-297.1(2\))20.9(-e)19.7(xp)20.8(re)19.7(ss)15.5(in)20.7(g)-300.6(h)0(u)20.8(m)0(a)18.5(n)-306.4(tu)20.7(mo)19.6(r)-300.6(c)0(e)18.5(l)0(l)20.6(s)]TJ T* [(in)20.7(je)19.5(ct)19.6(ed)-285.6(in)20.7(tr)15(av)19.7(en)19.7(ou)20.8(sl)20.9(y)-294.8(i)0(n)-284.6(m)0(i)19.5(c)0(e)-286.8(b)0(u)20.8(t)-295(no)15.1(t)-289.2(s)0(t)15.1(a)0(t)19.5(i)0(s)20.9(t)0(i)20.6(c)0(a)18.5(l)0(l)14.8(y)-294.8(si)20.9(gn)20.8(i)20.9(ca)18.5(nt)]TJ 0 -1.1174 TD [(co)19.7(mp)19.6(ar)19.7(ed)-297.1(wi)14.1(th)-296.1(th)20.7(e)-307.5(c)0(o)13.9(n)0(t)20.7(r)0(o)20.9(l)-306.5(\(B)19.8(el)13.8(ou)20.8(so)21(va)]TJ /F7 1 Tf 15.6434 0 TD [(et)-303(al)20.7(.)]TJ /F4 1 Tf 2.0332 0 TD [(,)-302.9(2)0(0)15.1(1)0(0)20.8(\))0(.)-298.2(T)0(h)19.6(e)-307.5(la)19.5(st)]TJ -17.6765 -1.1116 TD [(n)21(di)20.7(ng)-272.9(in)20.7(di)20.7(ca)18.5(te)13.8(s)-277.4(t)0(h)15(a)0(t)-268.4(t)0(h)20.7(e)0(r)14(e)-278.7(is)-272.8(a)-284.5(n)0(e)19.7(e)0(d)-274.1(t)0(o)-267.3(i)0(m)19.5(p)0(r)15.1(o)0(v)20.8(e)-278.7(th)15(e)-278.7(v)0(e)19.7(c)0(t)13.8(o)0(r)-267.1(t)0(o)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(CIRCUMVENTING)-339.9(ANTIVECTOR)-341.1(IMMUNITY)]TJ 53.0113 0 TD (291)Tj ET endstream endobj 22 0 obj <> endobj 23 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 24 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(ac)18.5(hi)20.7(ev)13.9(e)-284.5(t)0(h)20.7(e)-284.5(de)19.7(si)20.9(re)19.7(d)-289.1(l)0(e)19.6(v)0(e)19.7(l)0(s)-272.8(o)0(f)-272.9(t)0(a)13.8(r)0(g)20.9(e)0(t)19.5(-)0(s)21.1(p)0(e)19.7(c)0(i)13.8()0(c)-273.9(t)0(r)20.7(a)0(n)19.7(s)0(d)21(u)0(c)13.9(t)0(i)20.6(o)0(n)20.8(.)-285.7(Pa)19.8(n)]TJ 0 -1.1174 TD [(6)-306.4(v)0(e)19.7(c)0(t)13.8(o)0(r)-295.9(d)0(e)19.7(m)0(o)19.6(n)0(s)21(t)0(r)15(a)0(t)19.5(e)0(d)-297.1(a)-307.5(be)19.7(tt)20.6(er)-302.8(ca)18.5(pa)19.7(ci)19.5(ty)-296.1(th)15(an)-297.1(HA)19.1(dV)20(-5)-295.9(ve)19.7(ct)13.8(or)]TJ 0 -1.1116 TD [(in)-388.2(tr)15(an)19.7(sd)21(uc)19.7(ti)20.6(on)-393.9(of)-388.1(br)20.9(ai)19.5(n)-398.5(t)0(u)15(m)0(o)19.6(r)-398.5(ce)18.5(ll)20.6(s)-398.3(a)0(n)13.9(d)-398.5(gl)20.7(io)20.7(ma)-390.5(ce)18.5(ll)20.6(s,)-390.2(in)15(di)20.7(-)]TJ T* [(ca)18.5(ti)20.6(ng)-405.4(th)20.7(at)-406.7(it)-405.6(is)-405.3(a)-417(p)0(r)20.9(o)0(m)19.6(i)0(s)15.1(i)0(n)20.7(g)-415.8(ve)19.7(ct)19.5(or)-405.3(ca)18.5(nd)20.8(id)20.7(at)13.8(e)-411.2(f)0(o)15.1(r)-410(th)15(e)-411.2(b)0(r)15.1(a)0(i)19.6(n)]TJ T* [(tu)20.7(mo)19.6(r)-254.5(t)0(h)20.7(e)0(r)19.7(a)0(p)13.9(y)-248.8(\(S)21(ko)15.1(g)]TJ /F7 1 Tf 8.4092 0 TD [(et)-245.4(al)20.7(.)]TJ /F4 1 Tf 1.9756 0 TD .2511 Tc [(,2)251.1(0)271.9(0)251.1(7)266.2(\))251.1(.)10.5(T)251.1(w)269.9(e)251.1(n)270.8(t)251.1(y)]TJ /F7 1 Tf 6.5545 0 TD 0 Tc (E1)Tj /F4 1 Tf 1.0943 0 TD [(-d)20.9(el)19.5(et)19.5(ed)-245.3(ve)19.7(ct)19.5(or)15.1(s)]TJ -18.0336 -1.1174 TD [(we)18.8(re)-314.3(ge)19.7(ne)19.7(ra)14(te)19.6(d)-323.6(f)0(r)20.9(o)0(m)-314.4(d)0(i)20.7(f)0(f)20.9(e)0(r)19.7(e)0(n)13.9(t)-318(Ad)14.2(Vs)-313.9(is)20.9(ol)20.7(at)19.5(ed)-314.4(fr)15.1(om)-308.7(ch)19.7(im)13.7(pa)19.7(n-)]TJ 0 -1.1116 TD [(ze)18.5(es)19.9(,)-251.1(b)0(o)20.8(n)0(o)20.8(b)0(o)20.8(s)0(,)-240.5(a)0(n)19.7(d)-243(go)20.8(ri)15(ll)20.6(as)19.9(,)-245.3(o)0(f)-238.3(w)0(h)20(i)0(c)19.6(h)-248.8(12)-238.3(co)19.7(ul)20.7(d)-248.8(b)0(e)-233.7(p)0(r)15.1(o)0(p)20.8(a)0(g)19.7(a)0(t)19.6(e)0(d)19.7(,)]TJ T* [(re)19.7(sc)14.1(ue)19.7(d,)-298.3(an)19.7(d)-312.1(e)0(x)19.7(p)0(a)13.9(n)0(d)20.8(e)0(d)-302.9(i)0(n)-301.8(H)0(E)18.8(K)0(2)20(9)0(3)-301.7(c)0(e)18.5(l)0(l)20.6(s)-311.9(\(R)19.8(oy)]TJ /F7 1 Tf 18.673 0 TD [(et)-303(al)20.7(.)]TJ /F4 1 Tf 2.0332 0 TD -.0208 Tc [(,)-335.3(2)-20.8(01)-20.8(1b)-20.8(\).)]TJ -20.7061 -1.1174 TD 0 Tc [(SA)20.1(dV)20(-7)-244.1(\(H)20(Ad)14.2(V)-249.6(G)-255.4(sp)21(ec)18.5(ie)19.6(s\))-243.9(wa)18.8(s)-254.3(p)0(r)20.9(o)0(p)15.1(o)0(s)21(e)0(d)-245.3(f)0(o)20.9(r)-254.5(ve)19.7(ct)19.6(or)20.9(in)20.7(g)-254.5(a)-255.7(fe)19.7(w)]TJ 0 -1.1116 TD [(ye)19.7(ar)19.7(s)-519.3(e)0(a)18.5(r)0(l)20.7(i)0(e)19.6(r)-519.4(\(P)21(ur)20.9(ka)19.7(ya)13.9(st)20.9(ha)]TJ /F7 1 Tf 11.2545 0 TD [(et)-510.3(al)20.7(.)]TJ /F4 1 Tf 2.2405 0 TD [(,)-510.3(2)0(0)15.1(0)0(5)20.8(b)0(\))20.9(,)-516(an)19.7(d)-519.5(w)0(a)18.8(s)-513.5(su)21(bs)15.3(e-)]TJ -13.495 -1.1116 TD [(qu)20.8(en)19.7(tl)14.8(y)-461.9(c)0(o)19.7(n)0(s)15.3(t)0(r)20.7(u)0(c)19.7(t)0(e)19.6(d)-467.6(as)-452.4(an)]TJ /F7 1 Tf 11.099 0 TD (E1)Tj /F4 1 Tf 1.0943 0 TD [(-d)20.9(el)19.5(et)13.8(ed)-452.6(ve)19.7(ct)19.5(or)-457.2(th)20.7(at)-458.5(co)19.7(ul)20.7(d)-467.6(b)0(e)]TJ -12.1933 -1.1174 TD 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[(R)15.2(e)0(c)24.3(e)0(n)25.4(t)0(l)20.6(y)16.2(,)-222.3(i)0(t)-209.8(w)0(a)24.6(s)-225.5(s)16.4(h)0(o)20.8(w)15.3(n)-225.7(t)16.1(ha)25.4(t)-225.9(h)16.2(um)25.4(an)25.4(s)-225.5(h)16.2(av)25.4(e)-226.9(l)16.1(ow)-210.4(se)25.6(ro)20.9(r)16.2(e)0(a)24.3(c)0(t)25.3(i)0(v)20.7(i)16.1(ty)]TJ -1.0137 -1.1116 TD [(ag)25.4(ai)25.3(ns)21(t)-778.8(s)0(i)20.9(m)15(ia)25.3(n-)26.6(de)25.4(ri)20.7(v)16.2(e)0(d)-769.4(\()0(S)21(A)15.3(dV)25.7(-1)20.9(1)16.2(,)-781(-1)20.9(6)16.2(\))-784.4(or)-768.2(ch)25.4(im)25.2(pa)19.7(n)16.2(z)0(e)24.3(e)0(-)]TJ T* [(de)25.4(ri)26.5(ve)25.4(d)-340.9(\()16.2(Ch)25.6(Ad)20(V)15.3(-)0(3)26.6(,)-337.5(-6)26.6(3\))-324.7(Ad)25.7(V)-336(v)0(e)19.7(c)15(to)26.5(rs)-324.5(co)25.4(mp)25.4(ar)25.5(ed)-325.9(wi)25.6(th)-324.9(HA)24.9(dV)]TJ 0 -1.1174 TD [(ve)25.4(ct)25.3(or)26.6(s)-415.6(\()16.2(rH)25.8(Ad)25.7(V-)20(5)16.2(,)-412.4(-)16.2(2)0(8)26.6(,)-412.4(-3)26.6(5\))-399.6(a)15(c)0(r)25.5(o)0(s)21(s)-409.8(m)15(u)0(l)26.5(t)0(i)26.3(p)0(l)20.7(e)-411.2(g)16.2(e)0(o)25.4(g)0(r)26.6(a)0(p)25.4(h)0(i)20.7(c)-411.2(r)16.2(e)0(-)]TJ 0 -1.1116 TD [(gi)26.5(on)26.6(s)-386.8(\()16.2(Qu)25.7(in)20.7(n)]TJ /F7 1 Tf 5.6503 0 TD [(e)15(t)-381.4(al)20.7(.)]TJ /F4 1 Tf 2.0908 0 TD [(,)-383.6(2)16.2(01)26.6(3\))26.6(.)-383.6(C)0(h)25.6(i)0(m)25.2(p)0(a)25.4(n)0(z)25.4(e)0(e)18.5(s)-381(a)15(n)0(d)-370.8(m)15(ac)18.5(a)15(q)0(u)26.6(e)0(s)-371.8(e)0(l)25.3(i)0(-)]TJ -7.741 -1.1116 TD [(ci)25.3(te)25.3(d)-398.5(a)-393.9(sy)26.8(st)20.9(e)15(m)0(i)25.2(c)-399.7(h)16.2(u)0(m)25.4(o)0(r)26.6(a)0(l)-383.6(b)0(u)26.6(t)-398.6(n)16.2(o)0(t)-382.5(s)0(y)21(s)16.4(te)25.3(mi)25.2(c)-399.7(c)15(el)19.5(l)16.1(u)0(l)26.5(a)0(r)-383.5(i)0(m)25.2(m)0(u)25.4(n)0(e)]TJ 0 -1.1174 TD [(re)25.5(sp)26.8(on)20.8(s)16.4(e)-284.5(to)-273(en)25.4(do)26.6(ge)25.4(no)20.8(u)16.2(s)-283.1(Ad)20(V)15.3(s)0(.)-275(T)15(he)-274.1(s)16.4(t)0(r)20.7(u)16.2(ct)25.3(ur)26.6(e)-290.2(o)16.2(f)-283.3(t)0(h)20.7(e)]TJ /F7 1 Tf 20.6082 0 TD -.015 Tc (E3)Tj /F4 1 Tf 1.3823 0 TD 0 Tc [(lo)26.5(cu)19.7(s)16.4(,)]TJ -21.9906 -1.1116 TD [(in)26.5(vo)26.6(lv)20.7(e)15(d)-450.4(i)16.1(n)-450.4(m)15(o)0(d)26.6(u)0(l)20.7(a)15(ti)26.3(ng)-434.2(th)20.7(e)-445.8(h)0(o)26.6(s)0(t)20.9()16.2(s)-450.2(r)16.2(es)19.9(p)16.2(o)0(n)26.6(s)0(e)-440.9(t)16.1(o)-450.3(i)16(nf)20.9(e)15(c)0(t)25.3(i)0(o)26.5(n)0(,)-436.5(i)0(s)]TJ T* [(sm)25.6(al)25.3(le)25.3(r)-335.1(i)0(n)-319.1(H)0(A)24.9(d)0(V)25.7(s)-335(th)26.5(an)-320.1(in)-319.1(ap)25.4(e)-336.3(A)15.3(dV)20(s)16.4(,)-331.7(wh)25.7(ic)19.6(h)-329.4(m)15(ay)-325.9(i)16.1(m)0(p)25.4(a)0(c)24.3(t)-335.3(t)16.1(h)0(e)]TJ 0 -1.1174 TD [(ab)25.4(il)26.3(it)20.6(y)-317.9(o)16.2(f)-323.6(t)16.1(he)-308.6(ap)25.4(e)-324.8(A)15.3(dV)25.7(s)-323.4(t)16.1(o)-323.6(e)15(va)25.4(de)-308.6(ho)26.6(st)-307.4(im)25.2(mu)25.4(ne)-308.6(d)16.2(e)0(t)19.5(e)15(ct)25.3(io)26.5(n)-323.6(a)15(nd)]TJ 0 -1.1116 TD [(el)25.3(im)25.2(in)26.5(at)25.3(io)20.7(n)-467.6(\()0(C)25.6(a)0(l)25.3(c)0(e)24.3(d)0(o)]TJ /F7 1 Tf 8.9275 0 TD [(et)-458.5(al)26.5(.)]TJ /F4 1 Tf 2.1772 0 TD .4703 Tc [(,2)470.3(0)496.9(0)470.3(9)491.1(\))486.5(.C)470.3(h)495.9(A)470.3(d)496(V)470.3(-)490.3(6)486.5(8s)470.3(h)491.3(o)486.5(w)470.3(e)494.9(dt)486.4(h)470.3(e)]TJ -11.1047 -1.1116 TD 0 Tc [(ab)25.4(il)26.3(it)20.6(y)-410(t)0(o)-399.7(t)0(r)26.5(a)0(n)19.7(s)16.4(du)26.6(ce)-401.9(im)25.2(ma)24.2(tu)26.5(re)-406.5(a)15(n)0(d)-399.6(m)0(a)24.2(t)0(u)26.5(r)0(e)-400.7(h)0(u)20.8(m)15(an)-400.8(DC)24.7(s,)-401.8(fo)26.6(l-)]TJ T* [(lo)26.5(we)24.6(d)-283.3(b)0(y)-272.9(s)16.4(ec)24.3(re)19.7(t)16.1(i)0(o)26.5(n)-283.3(of)-272.9(I)16.2(F)0(N)20.1(-)]TJ /F8 1 Tf 10.7419 0 TD (a)Tj /F4 1 Tf .7833 0 TD [(an)25.4(d)-283.3(I)0(L)25.4(-)0(6)-272.9(b)16.2(ut)-273(n)16.2(o)0(t)-273(I)0(L)25.4(-)0(1)26.6(2)-283.3(or)-272.9(t)16.1(u)0(m)25.4(o)0(r)]TJ -11.5252 -1.1174 TD [(ne)25.4(cr)25.5(os)21(i)16.1(s)-277.4(fa)25.5(ct)25.3(or)-267.1(\(T)25.4(NF)25.9(\)-)]TJ /F8 1 Tf 8.8354 0 TD (a)Tj /F4 1 Tf .4838 0 TD [(,)-279.9(a)15(nd)-267.1(t)16.1(r)0(a)25.5(n)0(s)21(d)16.2(uc)25.4(ed)-268.3(i)16.1(m)0(m)24.1(a)0(t)25.3(u)0(r)20.9(e)-273(DC)18.9(s)-277.4(c)15(ou)26.6(ld)]TJ -9.3192 -1.1116 TD [(st)26.7(im)25.2(ul)26.5(at)19.5(e)-503.4(p)16.2(ro)26.6(li)20.6(f)16.2(e)0(r)25.5(a)0(t)25.3(i)0(o)20.7(n)-502.2(o)16.2(f)-502.2(au)19.7(t)16.1(o)0(l)26.5(o)0(g)26.6(o)0(u)20.8(s)-502(T)-503.4(l)16.1(ym)25.4(ph)26.6(oc)19.7(y)16.2(t)0(e)25.3(s)-502(\(V)20(a)15(r)0(-)]TJ T* [(na)25.4(vs)26.8(ki)]TJ /F7 1 Tf 2.8165 0 TD [(e)15(t)-266.2(al)26.5(.)]TJ /F4 1 Tf 1.9698 0 TD [(,)-268.4(2)16.2(00)20.8(3)16.2(\))0(.)-252.2(T)0(h)25.4(e)0(r)25.5(e)0(f)19.7(o)16.2(re)25.5(,)-268.4(C)15.2(hA)25.7(dV)25.7(-6)20.9(8)-260.3(c)0(o)19.7(u)16.2(ld)-250(be)-256.8(u)16.2(s)0(e)19.9(d)-260.3(as)-256.6(a)]TJ -4.7863 -1.1174 TD [(ve)25.4(ct)25.3(or)-307.4(fo)20.9(r)-317.8(t)0(r)26.5(a)0(n)25.4(s)0(d)26.8(u)0(c)19.7(t)16.1(io)26.5(n)-323.6(o)16.2(f)-323.6(h)16.2(um)25.4(an)-308.6(DC)24.7(s.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 358.0157 Tm [(Fowl)-338.7(AdV)-329(vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 72 341.5747 Tm [(Construction)-637.6(of)-635.7(FAdV)-633.8(\(genus)]TJ /F7 1 Tf 13.7023 0 TD [(Aviadenovi)-10.2(rus)]TJ /F4 1 Tf 5.7943 0 TD [(,)-637(species)]TJ -20.5103 -1.1116 TD [(FAdV)-282.5(A)-284.2(t)0(o)-284.6(FAdV)-282.5(E\))-285.6(vectors)-280.6(started)-286.5(with)-287.8(the)-281.1(demonstration)]TJ T* [(that)-276.5(recombinant)-282(FAdV-10)-280(\(FAdV)-277.8(C)-272.8(species\))-282.7(could)-277.5(be)-274.1(used)]TJ 0 -1.1174 TD [(to)-474.6(express)-476.1(an)-475.7(antigen)-476.8(to)-474.6(induce)-481.4(a)-474.6(protective)-475.6(immune)-476.9(re-)]TJ 0 -1.1116 TD [(sponse)-433.6(in)-428.5(pathogen-free)-433.7(chickens)-426.9(\(Sheppard)]TJ /F7 1 Tf 18.84 0 TD [(et)-429.7(al.)]TJ /F4 1 Tf 2.1887 0 TD [(,)-429.6(1998\).)]TJ -21.0287 -1.1116 TD [(After)-451.1(the)-453.8(identication)-456(of)-451.4(FAdV-9)-451.7(\(species)-455.5(FAdV)-449.5(D\))-452.3(re-)]TJ 0 -1.1174 TD [(gions)-402.9(that)-403.2(are)-397.3(nonessential)-408.4(for)-400.7(the)-402(virus)-402.8(\(Ojkic)-400.5(and)-401.9(Nagy,)]TJ 0 -1.1116 TD [(2001,)-439.8(2003;)-443.4(Corredor)-442.9(and)-442.2(Nagy,)-441.9(2010a\),)-437.4(FAdV-9)-445.9(recom-)]TJ T* [(binants)-279.6(demonstrated)-288.7(wild-type)-277.3(growth)-284(kinetics,)-279.7(virus)-281.9(titers,)]TJ 0 -1.1174 TD [(cytopathic)-567.8(effect)-574.6(and)-563.2(plaque)-567.8(morphology)-565.3(\(Corredor)-570.7(and)]TJ 0 -1.1116 TD [(Nagy,)-476.4(2010a\),)-472(expression)-479.6(in)-474.6(avian)-474.5(and)-471(mammalian)-478.1(cells,)]TJ T* [(and)-321.2(lack)-317.9(of)-319(replication)-321.4(in)-319.1(mammalian)-322.6(cells,)-316.6(indicating)-319.1(their)]TJ 0 -1.1174 TD [(applicability)-352.7(as)-348.7(gene)-346.6(delivery)-351.2(vehicles)-346.4(for)-348.8(mammalian)-351.4(sys-)]TJ 0 -1.1116 TD [(tems)-352.3(\(Corredor)-357.6(and)-350(Nagy,)-349.7(2010b\).)-355.6(FAdV-8)-353.7(\(species)-351.8(FAdV)]TJ T* [(E\))-487.2(vectors)-493.8(were)-491.4(also)-489.3(constructed)-493.7(and)-488.3(showed)-486.5(efcacious)]TJ /F7 1 Tf T* [(in)-422.8(vivo)]TJ /F4 1 Tf 3.3003 0 TD [(delivery)-420.3(of)-416.9(antibody)-424.9(fragments)-422.3(against)-419(pathogenic)]TJ -3.3003 -1.1174 TD [(infectious)-664.4(bursal)-658.5(disease)-661.8(virus)-656.3(\(Greenall)]TJ /F7 1 Tf 18.385 0 TD [(et)-654.3(al.)]TJ /F4 1 Tf 2.4133 0 TD [(,)-660(2010\).)]TJ -20.7983 -1.1116 TD [(FAdV-1)-549.6(\(species)-553.4(FAdV)-553.2(A\))-550.2(or)-549.3(CELO)-550.1(\(Chicken)-553.7(Embryo)]TJ T* [(Lethal)-384.8(Orphan\))-384.1(vectors)-378.6(have)-386.9(been)-381.1(widely)-377.5(used.)-383.2(The)-380(geno-)]TJ 0 -1.1174 TD [(mic)-293.8(regions)-296.8(that)-293.8(could)-300.5(be)-291.3(deleted)-299.4(were)-295.6(evaluated)-297(more)-294.8(than)]TJ 0 -1.1116 TD [(10)-255.6(years)-261(ago)-252.1(and)-257.9(a)-255.7(cosmid-based)-265.3(strategy)-258.8(was)-252.8(developed)-261.2(for)]TJ T* [(generating)-469.8(CELO)-469.5(vectors)-470.7(\()-87.5(Michou)]TJ /F7 1 Tf 15.1538 0 TD [(et)-464.3(al.)]TJ /F4 1 Tf 2.2232 0 TD [(,)-470(1999;)-466.4(Franc)]TJ 5.3623 0 TD [()-52.9(ois)]TJ /F7 1 Tf -22.7393 -1.1174 TD [(et)-389.4(al.)]TJ /F4 1 Tf 2.1484 0 TD [(,)-389.3(2001\).)-389.1(FAdV-1)-388.3(has)-390.2(several)-391.2(interesting)-389.1(properties:)-394.7(it)]TJ -2.1484 -1.1116 TD [(interacts)-681.7(with)-673.7(CAR)-680.1(and)-678.4(its)-671.5(capsid)-682.8(architecture)-681.7(allows)]TJ T* [(changes)-558.2(in)-555.3(its)-556.3(tropism)-556.1(\(Tan)]TJ /F7 1 Tf 12.6886 0 TD [(et)-556.4(al.)]TJ /F4 1 Tf 2.3154 0 TD [(,)-556.4(2001\),)-550.3(it)-555.4(transduces)]TJ -15.004 -1.1174 TD [(mammalian)-265(cells)-267.1(as)-262.4(efciently)-268.1(as)-262.4(HAdV-5)-268.4(vector,)-265.9(and)-263.7(it)-261.6(has)]TJ 0 -1.1116 TD [(a)-457.3(potential)-456.3(for)-452.5(mammalian)-460.9(gene)-450.2(transfer)-460.2(applications,)-458.2(es-)]TJ 25.504 67.9184 TD [(pecially)-329.5(because)-334.7(it)-325(has)-326.8(larger)-325.8(DNA)-328.5(packaging)-330.3(capacity)-330.5(and)]TJ 0 -1.1174 TD [(greater)-587.2(physical)-575.7(stabil)-8(ity)-573.8(\()-87.5(Michou)]TJ /F7 1 Tf 15.2229 0 TD [(et)-579.5(al.)]TJ /F4 1 Tf 2.3384 0 TD [(,)-579.4(1999\).)-573.4(It)-578.3(was)]TJ -17.5613 -1.1116 TD [(shown)-449.7(that)-449.3(FAdV-1)-451.7(is)-451.4(able)-444.6(to)-451.6(deliver)-448(p53)-446.8(transgene)-456.8(into)]TJ T* [(various)-544.4(tissues)]TJ /F7 1 Tf 6.6928 0 TD [(in)-538(vivo)]TJ /F4 1 Tf 3.5307 0 TD [(restoring)-541(p53)-539(function)-540.1(in)-538(human)]TJ -10.2235 -1.1116 TD [(tumor)-387(cell)-381.4(xenografts)-381.8(in)-382.5(mice)-382.5(and)-384.6(leading)-378.9(therefore)-387.8(to)-382.5(the)]TJ 0 -1.1174 TD [(inhibition)-414.8(of)-411.1(tumor)-410(growth)-410.8(\(Logunov)]TJ /F7 1 Tf 15.9717 0 TD [(et)-412.4(al.)]TJ /F4 1 Tf 2.1714 0 TD [(,)-406.6(2004\).)-412.1(More-)]TJ -18.1431 -1.1116 TD [(over,)-371.8(FAdV-1)-371(encod)-7.8(ing)-366.3(the)-373.2(human)]TJ /F7 1 Tf 14.8428 0 TD (IL-2)Tj /F4 1 Tf 2.085 0 TD [(gene)-375.4(can)-368.5(success-)]TJ -16.9278 -1.1116 TD [(fully)-322.5(produce)-321(biologically)-321.5(active)-321.4(recombinant)-322.3(IL-2)]TJ /F7 1 Tf 21.0517 0 TD [(in)-313.3(vitro)]TJ /F4 1 Tf 2.995 0 TD (,)Tj /F7 1 Tf -24.0468 -1.1174 TD [(in)-347.9(ovo)]TJ /F4 1 Tf 2.5804 0 TD [(,)-343.2(and)]TJ /F7 1 Tf 2.3903 0 TD [(in)-342.1(vivo)]TJ /F4 1 Tf 2.805 0 TD [(,)-343.3(and)-350(it)-342.3(is)-347.7(capable)-352.3(of)-347.7(increasing)-348.6(the)-350.2(me-)]TJ -7.7756 -1.1116 TD [(dian)-639.3(survival)-632.1(time)-640.6(of)-630(mice)-635.9(carrying)-639(melanoma)-637(tumors)]TJ T* (\(Shmarov)Tj /F7 1 Tf 4.3831 0 TD [(et)-429.7(al.)]TJ /F4 1 Tf 2.1887 0 TD [(,)-429.6(2002;)-426.1(Cherenova)]TJ /F7 1 Tf 8.1615 0 TD [(et)-429.7(al.)]TJ /F4 1 Tf 2.1887 0 TD [(,)-429.6(2004\).)-429.4(Also,)-429.1(re-)]TJ -16.922 -1.1174 TD [(combinant)-399.6(FAdV-1)-394.1(encoding)-397.2(the)-396.2(HSV-1)-393(thymidine)-398.6(kinase)]TJ 0 -1.1116 TD [(showed)-331(cytotoxicity)-327.2(in)-330.6(carcinoma)-326.9(cell)-329.5(lines)-329.3(and)-327(suppressed)]TJ T* [(tumor)-306.3(growth)-307.1(and)-304(increase)-307.1(median)-304(of)-301.7(survival)-309.5(of)-301.7(mice)-307.6(with)]TJ T* [(melanoma)-395(tumors)-387.9(\(Shashkova)]TJ /F7 1 Tf 12.7981 0 TD [(et)-389.4(al.)]TJ /F4 1 Tf 2.1484 0 TD [(,)-389.3(2005\),)-383.3(demonstrating)]TJ -14.9464 -1.1174 TD [(its)-314.4(efcacy)-317.4(for)-314.3(the)-315.6(gene)-312(delivery)-316.6(to)-313.4(tumor)-312.1(cells)]TJ /F7 1 Tf 19.5427 0 TD [(in)-313.4(vitro)]TJ /F4 1 Tf 3.3061 0 TD (and)Tj /F7 1 Tf -22.8487 -1.1116 TD [(in)-399.7(vivo)]TJ /F4 1 Tf 2.8568 0 TD [(.)-395.1(Furthermore,)-399.1(one)-390.4(study)-397.1(showed)-394.4(that)-397.5(FAdV-1)-399.8(suc-)]TJ -2.8568 -1.1116 TD [(cessfully)-507.4(enhanced)-503(expression)-502.6(levels)-504.3(of)-497.5(secreted)-502.9(alkaline)]TJ 0 -1.1174 TD [(phosph)-6.4(atase)-435.1(reporter)-437.4(gene)-432.9(in)-434.3(transduced)-440.6(mammalian)-437.8(cells)]TJ /F7 1 Tf 0 -1.1116 TD [(in)-411.3(vitro)]TJ /F4 1 Tf 3.4904 0 TD (and)Tj /F7 1 Tf 1.8546 0 TD [(in)-405.5(vivo)]TJ /F4 1 Tf 3.2715 0 TD (\(Tutykhina)Tj /F7 1 Tf 4.8669 0 TD [(et)-406.7(al.)]TJ /F4 1 Tf 2.1657 0 TD [(,)-406.6(2008\).)-406.3(Finally,)-410(PE-)]TJ -15.6491 -1.1116 TD [(Gylated)-270.4(and)-257.9(retargeted)-269.3(with)-264.7(broblast)-264.4(growth)-261(factor,)-265.9(FAdV-)]TJ 0 -1.1174 TD [(1)-248.8(showed)-250.4(increased)-250.6(levels)-250.9(of)-244.1(binding)-249.9(and)-246.4(internalization)-252.3(in)-244.2(a)]TJ 0 -1.1116 TD [(variety)-425(of)-416.9(human)-416.8(cell)-421.7(lines)-421.4(\(Stevenson)]TJ /F7 1 Tf 16.6686 0 TD [(et)-418.2(al.)]TJ /F4 1 Tf 2.1772 0 TD [(,)-418.1(2006\),)-417.9(with)]TJ -18.8458 -1.1116 TD [(transgene)-612.3(expression)-606.3(being)-605.8(greater)-604.5(than)-604.7(the)-609.4(unmodied)]TJ 0 -1.1174 TD [(version)-429.2(in)-422.8(PC-3)-425.7(human)-428.4(prostate)-425.9(cells,)-431.8(and)-424.9(being)-427.3(fully)-420.4(re-)]TJ 0 -1.1116 TD [(sistant)-475.4(to)-463.1(inhibition)-472.4(by)-463(human)-468.7(serum)]TJ /F7 1 Tf 16.2366 0 TD [(in)-463.1(vitro)]TJ /F4 1 Tf 3.6113 0 TD (\(Stevenson)Tj /F7 1 Tf -19.8479 -1.1116 TD [(et)-251.2(al.)]TJ /F4 1 Tf 2.0101 0 TD [(,)-251.1(2006\).)-250.8(All)-246.3(together)-253.3(indicates)-255.5(that)-247.7(retargeting)-252.1(of)-249.8(CELO)]TJ -2.0101 -1.1116 TD [(virus)-339.5(to)-336.4(human)-336.2(cells)-342(via)-332.9(disease-specic)-345.5(receptors)-341.6(is)-336.2(possi-)]TJ 0 -1.1174 TD [(ble,)-336.3(while)-336.1(avoiding)-332.8(preexisting)-337.2(humoral)-338.5(immunity.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 390.8975 Tm [(Ovine)-337.2(AdV)-335.3(vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 323.0361 374.4566 Tm [(The)-270.6(production)-277.4(of)-267.1(OAdV)-272(\(genus)]TJ /F7 1 Tf 13.4144 0 TD (Mastadenovirus)Tj /F4 1 Tf 6.4509 0 TD [(,)-268.4(species)]TJ -20.8789 -1.1116 TD [(OAdV)-289.3(A,)-287.6(B;)-291.4(genus)]TJ /F7 1 Tf 8.0521 0 TD (Atadenovirus)Tj /F4 1 Tf 5.345 0 TD [(,)-285.7(species)-293.2(OAdV)-289.2(D\))-285.3(vectors)]TJ -13.3971 -1.1174 TD [(starte)-9(d)-381.2(more)-386.9(than)-385.8(15)-388.1(years)-387.7(ago)-384.6(\(Xu)]TJ /F7 1 Tf 15.2863 0 TD [(et)-383.6(al.)]TJ /F4 1 Tf 2.1426 0 TD [(,)-383.6(1997\))-385.6(after)-393.8(de-)]TJ -17.4289 -1.1116 TD [(termining)-271.9(the)-275.3(nonessential)-270.1(regions)-273.7(within)-272.8(the)-269.5(genome)-269.4(\(Vrati)]TJ /F7 1 Tf T* [(et)-383.6(al.)]TJ /F4 1 Tf 2.1426 0 TD [(,)-377.8(1996\).)-377.5(Surprisingly,)-379.5(much)-375.4(larger)-383.4(insertions)-380.8(than)-380.1(ex-)]TJ -2.1426 -1.1116 TD [(pected)-384.6(are)-380(tolerated,)-385.8(and)-378.8(portions)-383.2(of)-382.3(sequences)-382.8(can)-380(be)-383.5(de-)]TJ 0 -1.1174 TD [(leted)-296.1(without)-297(affecting)-295.8(virus)-293.4(viability)-293.9(\(Xu)]TJ /F7 1 Tf 17.2618 0 TD [(et)-291.5(al.)]TJ /F4 1 Tf 2.0505 0 TD [(,)-291.4(1997\).)-296.9(The)]TJ -19.3123 -1.1116 TD [(primary)-540.1(receptor)-536.5(for)-538.9(OAdV-7)-539.1(\(OAdV)-538(D)-531.9(species\))-541.9(is)-532(not)]TJ T* [(CAR,)-320.7(as)-314.2(it)-313.5(was)-316.2(shown)-311.5(that)-316.9(OAdV-7)-314.5(does)-316.4(not)-314.5(compete)-317.8(with)]TJ 0 -1.1174 TD [(HAdV-5)-297.2(for)-291.2(the)-292.6(entry)-289(into)-292.6(cells)-295.9(\(Xu)-286.4(and)-292.5(Both,)-291.2(1998;)-293.6(Voeks)]TJ /F7 1 Tf 0 -1.1116 TD [(et)-395.1(al.)]TJ /F4 1 Tf 2.1541 0 TD [(,)-395.1(2002\).)-394.8(Recombinant)-398.3(OAdVs)-393.8(can)-397.3(infect)-395.1(a)-393.9(variety)-396.2(of)]TJ -2.1541 -1.1116 TD [(nonovine)-344.2(cells)-342(such)-345.2(as)-337.2(rabbit,)-345.5(human,)-339.6(and)-344.3(murine)-337.4(cells)-342(but)]TJ 0 -1.1174 TD [(canno)-7.8(t)-323.8(replicate)-331.7(within)-324.6(them)-329.5(\(Khatri)]TJ /F7 1 Tf 15.2459 0 TD [(et)-326(al.)]TJ /F4 1 Tf 2.085 0 TD [(,)-326(1997;)-322.4(Hofmann)]TJ /F7 1 Tf -17.331 -1.1116 TD [(et)-245.4(al.)]TJ /F4 1 Tf 2.0044 0 TD [(,)-239.6(1999;)-241.8(Lo)]TJ 3.7093 .023 TD ()Tj .4147 -.023 TD (ser)Tj /F7 1 Tf 1.4111 0 TD [(et)-239.6(al.)]TJ /F4 1 Tf 1.9986 0 TD [(,)-239.6(2000;)-241.8(Xu)]TJ /F7 1 Tf 4.4695 0 TD [(et)-245.4(al.)]TJ /F4 1 Tf 2.0044 0 TD [(,)-239.6(2000;)-241.8(Ku)]TJ 3.8129 .0115 TD ()Tj .4147 -.0115 TD (min)Tj /F7 1 Tf 1.8028 0 TD [(et)-245.4(al.)]TJ /F4 1 Tf 2.0044 0 TD (,)Tj -24.0468 -1.1116 TD [(2002;)-299.4(Lockett)-299.5(and)-298.2(Both,)-297(2002\).)-296.9(They)-294.8(are)-299.3(not)-297.2(neutralized)-299.3(by)]TJ 0 -1.1174 TD [(polyclonal)-290.2(serum)-289.9(against)-292.3(HAdV-5)-285.7(\(Xu)-286.4(and)-286.7(Both,)-291.2(1998\))-287.7(and)]TJ 0 -1.1116 TD [(they)-449.2(can)-443.4(overcome)-445.5(preexisting)-446.6(humoral)-442.2(immunity)-443.6(against)]TJ T* (HAdVs)Tj /F7 1 Tf 3.5249 0 TD [(in)-480.4(vivo)]TJ /F4 1 Tf 3.4213 0 TD (\(Hofmann)Tj /F7 1 Tf 4.5962 0 TD [(et)-487.3(al.)]TJ /F4 1 Tf 2.2463 0 TD [(,)-481.5(1999\).)-481.2(A)-480(cosmid-based)]TJ -13.7887 -1.1116 TD [(system)-250.6(proved)-249.6(useful)-249.6(for)-245.1(efcient)-254.3(generation)-250.9(of)-244.1(recombinant)]TJ 0 -1.1174 TD [(OAdVs)-330.5(and)-327(vectors)-326.7(could)-329.3(be)-320.1(rescued)-333.5(in)-324.9(an)-325.9(ovine)-323.6(fetal)-330.6(skin)]TJ 0 -1.1116 TD [(brobl)-6.6(astic)-318.9(producer)-322.1(cell)-323.8(line)-316.8(\(Lo)]TJ 13.351 .023 TD ()Tj .4205 -.023 TD (ser)Tj /F7 1 Tf 1.4802 0 TD [(et)-320.3(al.)]TJ /F4 1 Tf 2.0793 0 TD [(,)-320.2(2003\).)-319.9(OAdV-7)]TJ -17.331 -1.1116 TD [(carrying)-633.2(purine)-624.2(nucleoside)-630.9(phosphorylase)-626.9(\(PNP\),)-625.7(which)]TJ 0 -1.1174 TD [(conve)-7.8(rts)-383.3(the)-379(prodrug)-387.8(udarabine)-383.1(into)-384.8(its)-383.5(activated)-389.3(form)-379.9(2-)]TJ 0 -1.1116 TD [(uoroadenin)-8.6(e,)-334(was)-339.2(effective)]TJ /F7 1 Tf 11.8477 0 TD [(in)-336.4(vivo)]TJ /F4 1 Tf 3.1275 0 TD [(against)-338.4(prostate)-339.5(cancer)]TJ -14.9752 -1.1116 TD [(progression)-577.4(upon)-568.9(prodrug)-572.1(addition)-569.1(\(Voeks)]TJ /F7 1 Tf 18.863 0 TD [(et)-573.7(al.)]TJ /F4 1 Tf 2.3327 0 TD [(,)-567.9(2002;)]TJ -21.1957 -1.1174 TD [(Martiniello)-10.2(-Wilks)]TJ /F7 1 Tf 7.8966 0 TD [(et)-648.6(al.)]TJ /F4 1 Tf 2.4076 0 TD [(,)-648.5(2004\).)-642.5(Moreover,)-649(recombinant)]TJ -10.3041 -1.1116 TD [(OAdV-7)-291.4(expressing)-289.5(ovalbumin)-283.3(showed)-284.9(efcacy)-288.6(in)-284.6(inducing)]TJ T* [(antitumor)-398.6(response)-396.6(in)-394(a)-393.9(mouse)-393.6(model)-393.9(\(Tang)]TJ /F7 1 Tf 18.9149 0 TD [(et)-395.1(al.)]TJ /F4 1 Tf 2.1541 0 TD [(,)-389.3(2012\).)]TJ -21.069 -1.1174 TD [(OAdVs)-360.3(biosafety)-363.6(prole)-359.1(and)-355.8(their)-358.2(application)-361.7(as)-354.5(gene)-358.1(de-)]TJ 0 -1.1116 TD [(livery)-238.4(vectors)-240.3(were)-238(reviewed)-237.9(in)-232.7(the)-240.7(last)-236(decade)-235.9(\(Both,)-234.7(2004\).)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (292)Tj 43.6471 0 TD [(LOPEZ-GORDO)-336.9(ET)-338.7(AL.)]TJ ET endstream endobj 25 0 obj <> endobj 26 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 27 0 obj <>stream /GS1 gs BT /F10 1 Tf 8.9663 0 0 8.9663 59.7543 725.7825 Tm 0 0 0 1 k 0 Tc 0 Tw [(Murine)-336.4(AdV)-335.3(vectors)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 709.3416 Tm [(The)-241.8(production)-248.6(of)-244.1(MAdV)-243.2(\(genus)]TJ /F7 1 Tf 13.4432 0 TD (Mastadenovirus)Tj /F4 1 Tf 6.4509 0 TD [(,)-239.6(species)]TJ -20.9077 -1.1116 TD [(Murine)-302.5(A,)-299.1(B,)-305.1(C\))-296.9(mutants)-303.9(started)-303.8(with)-299.3(the)-304.1(MAdV-1)-297.2(\()-87.5(MAdV)]TJ 0 -1.1174 TD [(A)-526.1(species\))]TJ /F7 1 Tf 4.9994 0 TD (E3)Tj /F4 1 Tf 1.1116 0 TD [(-deleted)-530.9(recombinant)-529.7(\(Beard)-522.5(and)-528.6(Spindler,)]TJ -6.111 -1.1116 TD [(1996;)-501(Cauthen)]TJ /F7 1 Tf 6.6294 0 TD [(et)-498.8(al.)]TJ /F4 1 Tf 2.2578 0 TD [(,)-498.8(1999\))-500.8(and)]TJ /F7 1 Tf 5.5293 0 TD (E1)Tj /F4 1 Tf 1.1174 0 TD [(-deleted)-502.1(recombinant)]TJ -15.5339 -1.1116 TD (\(Ying)Tj /F7 1 Tf 2.5688 0 TD [(et)-239.6(al.)]TJ /F4 1 Tf 1.9986 0 TD [(,)-233.8(1998\).)-239.3(MAdV-1)-233.9(presents)-241.2(mouse)-238.1(endothelial)-240.8(cell)]TJ -4.5674 -1.1174 TD [(tropism)-377.6(\(Charles)]TJ /F7 1 Tf 7.2054 0 TD [(et)-372.1(al.)]TJ /F4 1 Tf 2.1311 0 TD [(,)-372(1998;)-368.5(Kajon)]TJ /F7 1 Tf 6.0938 0 TD [(et)-372.1(al.)]TJ /F4 1 Tf 2.1311 0 TD [(,)-372(1998;)-368.5(Lenaerts)]TJ /F7 1 Tf -17.5613 -1.1116 TD [(et)-354.8(al.)]TJ /F4 1 Tf 2.1138 0 TD [(,)-349(2005\),)-354.5(but)-349(it)-353.8(can)-351.2(also)-351.1(infect)-354.7(human)-353.5(endothelial)-356(cells)]TJ -2.1138 -1.1116 TD (\(Nguyen)Tj /F7 1 Tf 4.003 0 TD [(et)-504.6(al.)]TJ /F4 1 Tf 2.2693 0 TD [(,)-498.8(1999\))-506.6(and)-505.6(it)-503.6(displays)-505.2(higher)-503.2(afnity)-504.3(for)]TJ -6.2723 -1.1116 TD [(primary)-672.5(human)-664.5(smooth)-670.1(muscle)-666.7(cells)-670.3(than)-668.1(recombinant)]TJ 0 -1.1174 TD [(HAdV-5)-423.9(\(Lenaerts)]TJ /F7 1 Tf 8.1269 0 TD [(et)-418.2(al.)]TJ /F4 1 Tf 2.1772 0 TD [(,)-423.9(2009\).)-417.9(MAdV-1)-423.9(lacks)-422.5(the)-425.1(RGD)]TJ -10.3041 -1.1116 TD [(motif)-318(in)-313.3(the)-309.9(penton)-313.2(base,)-315.2(but)-314.5(it)-313.5(contains)-316.5(it)-313.5(in)-307.6(the)-315.6(ber)-316.4(knob)]TJ T* [(domain)-314.4(\(Raman)]TJ /F7 1 Tf 6.808 0 TD [(et)-308.8(al.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-302.9(2009\).)-308.4(The)-310.9(RGD)-311.3(motif)-306.5(was)-310.4(reported)]TJ -8.8757 -1.1174 TD [(to)-445.8(play)-449.2(a)-445.8(role)-449.2(in)-445.8(MAdV-1)-447(infection)-444.6(through)]TJ /F8 1 Tf 19.2144 0 TD (a)Tj /F4 1 Tf 7.3823 0 0 6.5614 253.7574 576.1699 Tm (v)Tj 9.843 0 0 9.843 261.8645 577.814 Tm (integrins,)Tj -20.5334 -1.1116 TD [(which)-318.7(act)-316.8(as)-314.2(a)-313.3(receptor)-317.6(for)-320(the)-315.6(virus,)-314.1(and)-315.5(it)-313.5(was)-316.2(shown)-317.2(that)]TJ T* [(cell)-594.5(surface)-598.4(heparan)-592.9(sulfate)-597.6(glycosaminoglycans)-595.9(are)-593.1(in-)]TJ 0 -1.1174 TD [(volved)-474.4(in)-474.6(MAdV-1)-475.8(infection)-473.4(\(Raman)]TJ /F7 1 Tf 16.2827 0 TD [(et)-475.8(al.)]TJ /F4 1 Tf 2.2348 0 TD [(,)-470(2009\).)-475.4(Con-)]TJ -18.5175 -1.1116 TD [(versely,)-330.2(the)-321.4(primary)-327(attachment)-328.3(of)-318.9(MAdV-1)-326(is)-324.7(independent)]TJ T* [(of)-324.7(CAR)-323(\(Lenaerts)]TJ /F7 1 Tf 7.6489 0 TD [(et)-320.3(al.)]TJ /F4 1 Tf 2.085 0 TD [(,)-320.2(2006\).)-325.7(Distribution)-325.5(of)-319(MAdV-1)-326(to)]TJ -9.7339 -1.1174 TD [(the)-459.6(liver)-461.9(is)-457.1(markedly)-456(lower)-462.7(in)-457.3(intravenously)-460.3(injected)-461.9(im-)]TJ 0 -1.1116 TD [(munodecient)-496.1(mice)-491.9(than)-489.5(that)-489.6(observed)-494.7(with)-489.3(recombinant)]TJ T* [(HAdV-5)-464.2(\(Lenaerts)]TJ /F7 1 Tf 8.2076 0 TD [(et)-458.5(al.)]TJ /F4 1 Tf 2.2175 0 TD [(,)-464.2(2009\).)-458.2(Moreo)-7.5(ver,)-457.1(MAdV-)-8.1(1)-456.1(has)]TJ -10.4251 -1.1116 TD [(been)-265.9(used)-258.8(as)-262.4(an)-256.8(oncolytic)-266.1(vector,)-260.1(proving)-261.2(that)-259.3(it)-261.6(is)-261.3(a)-255.7(suitable)]TJ 0 -1.1174 TD [(murine)-366.2(homolog)-366.2(model)-365.1(to)-365.2(test)-362.7(the)-361.7(mechanism)-372.9(of)-359.3(action)-366.3(of)]TJ 0 -1.1116 TD [(murine)-562(oncolytic)-565.6(AdV)-563.7(vectors)-562.9(in)-561(an)-562.1(immunocompetent,)]TJ T* [(tumor-bearing)-484.6(host)-476.6(\(Robinson)]TJ /F7 1 Tf 13.0054 0 TD [(et)-481.5(al.)]TJ /F4 1 Tf 2.2405 0 TD [(,)-475.7(2009\).)-475.4(Furthermore,)]TJ -15.2459 -1.1174 TD [(MAdV-1)-447(has)-442(preference)-448.7(for)-441(ovarian)-447.9(carcinoma)-442.1(cell)-444.7(lines,)]TJ 0 -1.1116 TD [(probably)-436.3(because)-438.4(of)-428.4(their)-433.1(increased)-440.7(expression)-433.5(of)-434.1(the)-430.8(en-)]TJ T* [(zyme)-359.3(involved)-361.6(in)-353.7(HSPG)-362.9(biosynthesis,)-357.4(therefore)-364.8(having)-353.5(the)]TJ 0 -1.1174 TD [(potential)-427.5(to)-422.8(be)-423.8(used)-425.8(in)-422.8(the)-425.1(oncolytic)-427.3(treatment)-429.7(of)-422.6(ovarian)]TJ 0 -1.1116 TD [(cancer)-339.5(\(Lenaerts)]TJ /F7 1 Tf 7.0844 0 TD [(et)-337.6(al.)]TJ /F4 1 Tf 2.0965 0 TD [(,)-331.7(2012\).)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 368.9007 Tm [(Concluding)-339(Remarks)-337.5(and)-331.9(Future)-334(Perspectives)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 352.4597 Tm [(Th)19.6(e)-560.9(m)0(a)18.4(i)0(n)-555.3(l)0(i)20.6(m)0(i)19.5(t)0(a)19.6(t)0(i)20.6(o)0(n)-549.4(o)0(f)-555.1(c)0(l)19.5(i)0(n)20.7(i)0(c)19.6(a)0(l)19.5(l)0(y)-555.3(a)0(p)19.7(p)0(l)20.7(i)0(e)19.6(d)-559.8(HA)19.1(dV)14.2(-b)20.9(as)19.9(ed)]TJ -1.0137 -1.1116 TD [(ve)13.9(ct)19.5(or)20.9(s)-369.5(t)0(o)20.7(d)0(a)19.7(y)-369.7(is)-359.2(th)20.7(ei)19.5(r)-369.7(f)0(a)19.7(i)0(l)20.6(u)0(r)20.9(e)-370.9(in)-359.4(ac)18.5(hi)20.7(ev)19.7(in)20.7(g)-369.7(h)0(i)20.7(g)0(h)-359.3(l)0(e)19.6(v)0(e)19.7(l)0(s)-359.2(o)0(f)-359.3(e)0(f)19.7(-)]TJ T* 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[(ci)13.8(rc)19.7(um)19.6(ve)19.7(nt)-388.2(th)20.7(is)20.9(,)-400.8(s)0(e)19.9(v)0(e)19.7(r)0(a)14(l)-398.6(st)20.9(ra)19.7(te)19.6(gi)14.9(es)-389.1(ha)19.7(ve)-389.3(be)19.7(en)-389.3(de)19.7(ve)19.7(lo)15(pe)19.7(d)-398.5(f)0(o)20.9(r)]TJ T* [(HA)13.3(dV)20(s,)-263.5(in)20.7(cl)19.5(ud)20.8(in)15(g)-271.8(m)0(o)19.6(l)0(e)19.5(c)0(u)19.7(l)0(a)19.6(r)-277.5(en)19.7(gi)20.7(ne)19.7(er)14(in)20.7(g)-271.8(o)0(f)-267.1(c)0(h)19.7(i)0(m)19.5(e)0(r)19.7(i)0(c)-262.7(v)0(e)13.9(c)0(t)19.5(o)0(r)20.9(s)]TJ 0 -1.1174 TD [(or)-232.6(th)20.7(e)-244.2(u)0(s)21(e)-238.4(of)-232.6(lo)20.7(w-)20(se)14.1(ro)20.9(pr)20.9(ev)19.7(al)19.5(en)13.9(t)-237.4(H)0(A)19.1(d)0(V)-233.5(v)0(e)19.7(c)0(t)19.5(o)0(r)20.9(s)0(.)]TJ 1.0137 -1.1116 TD [(As)-365.7(an)-360.5(alternative,)-372(NHAdV)-366.1(vectors)-361.3(have)-363.8(been)-369.6(developed)]TJ -1.0137 -1.1116 TD [(and)-384.6(are)-385.7(being)-386.9(tested)-383.4(in)-382.5(various)-388.9(nonhuman)-379.8(and)-384.6(human)-388(cell)]TJ 0 -1.1174 TD [(lines.)-563.1(Most)-558.2(of)-555.1(the)-557.5(NHAdV)-561.9(vectors)-562.9(have)-553.9(two)-563(important)]TJ 0 -1.1116 TD [(features)-634.2(that)-627.9(make)-630(them)-629(more)-628.8(appropriate)-632.1(than)-633.5(HAdV)]TJ T* [(vectors:)-541.1(there)-543.6(is)-537.8(no)-537.9(or)-537.8(very)-541.2(low)-539.9(pathogenicity)-542.5(for)-538.9(their)]TJ 0 -1.1174 TD [(natural)-350.1(host,)-341.8(and)-344.3(there)-342(is)-342(no)-342(presence)-347.3(of)-347.8(preexisting)-342.9(NAbs,)]TJ 0 -1.1116 TD (CD4)Tj /F9 1 Tf 1.941 0 TD (+)Tj /F4 1 Tf 1.0367 0 TD [(T)-313.3(cells,)-322.4(and)-315.5(CD8)]TJ /F9 1 Tf 7.1536 0 TD (+)Tj /F4 1 Tf 1.0367 0 TD [(CTLs)-318.7(against)-315.4(them.)-315.6(However,)-320.5(it)]TJ -11.1681 -1.1116 TD [(should)-427(be)-418.1(noted)-421.5(that)-426.3(caution)-425(must)-420.3(be)-423.8(applied)-419.2(when)-426.9(using)]TJ T* [(nonhuman)-270.4(primate)-270.7(AdVs,)-268.6(since)-267(their)-271.8(ability)-268.6(to)-267.3(infect)-268.3(human)]TJ 0 -1.1174 TD [(cells)-399.6(and)-390.4(their)-392.8(structural)-399.4(similarity)-394(could)-398.5(potentially)-395.2(result)]TJ 0 -1.1116 TD [(in)-330.6(anti-HAdV)-330.7(T-cell)-332.9(and/or)-330.4(NAb)-333.4(cross-reactivity)-333.3(with)-333.8(non-)]TJ T* [(human)-606.9(primate)-610.5(AdV)-604.1(antigens.)-607.9(Different)-606.5(NHAdVs)-608.9(have)]TJ 0 -1.1174 TD [(specic)-345(tropism)-337.3(for)-337.3(different)-340.7(cell)-341(types,)-338.3(which)-336(makes)-342.9(them)]TJ 0 -1.1116 TD [(applicable)-315.6(in)-301.8(treating)-311(different)-311.9(diseases)-311.3(especially)-309.6(when)-305.9(the)]TJ 25.5097 67.9242 TD [(targeting)-490.6(of)-491.7(specic)-489(cells)-497.5(is)-485.9(required,)-492.7(and)-494(therefore)-491.5(they)]TJ 0 -1.1174 TD [(could)-386.9(extend)-383.4(the)-390.5(range)-387.9(of)-382.3(potential)-387.1(target)-389.3(tissues.)-392.1(Further-)]TJ 0 -1.1116 TD [(more,)-563.1(the)-563.3(inability)-558.9(of)-560.9(NHAdVs)-568.6(to)-561(co-replicate)-566.5(with)-564.2(wt)]TJ T* [(HAdVs,)-241.8(as)-239.3(well)-242.9(as)-245.1(the)-240.7(fact)-243(that)-242(they)-241.8(are)-241.7(replication)-246.5(defective)]TJ T* [(in)-313.3(human)-313.2(cells,)-316.6(makes)-314.1(their)-317.9(vectors)-315.2(much)-317.8(safer)-312.8(than)-316.7(HAdV)]TJ 0 -1.1174 TD [(vectors.)-416.6(Many)-415.4(of)-411.1(the)-413.5(NHAdVs)-418.9(are)-414.5(able)-415.8(to)-411.3(tolerate)-415.8(longer)]TJ 0 -1.1116 TD [(sequences)-267.6(of)-261.4(exogenous)-271.2(DNA)-265.1(than)-264.9(HAdVs.)-264.8(For)-262.3(some)-265.8(of)-267.1(the)]TJ T* [(NHAdVs,)-295.6(there)-290.2(are)-293.6(low-cost)-298.9(propagation)-291.1(systems)-297.6(available,)]TJ 0 -1.1174 TD [(for)-268.2(example,)-275.2(chicken)-270.5(embryos)-274.8(for)-268.2(CELO)-273.7(virus)-270.4(\(Laver)]TJ /F7 1 Tf 22.0078 0 TD [(et)-274.2(al.)]TJ /F4 1 Tf 2.0332 0 TD (,)Tj -24.041 -1.1116 TD [(1971;)-305.1(Michou)]TJ /F7 1 Tf 6.0074 0 TD [(et)-308.8(al.)]TJ /F4 1 Tf 2.0677 0 TD [(,)-308.7(1999\).)-308.4(Despite)-310.5(these)-307.3(advantages,)-312.8(there)]TJ -8.0751 -1.1116 TD [(are)-512.4(still)-512.7(many)-513.6(steps)-513.3(necessary)-515.2(before)-515.7(using)-512.3(the)-511.5(NHAdV)]TJ 0 -1.1174 TD [(vectors)-367(in)-365.2(the)-367.5(clinics.)-370.8(The)-368.5(rst)-367(challenge)-371.9(is)-365(to)-370.9(nd)-366(the)-367.5(ap-)]TJ 0 -1.1116 TD [(propriate)-386.8(cell)-387.1(lines)-386.9(for)-383.4(efcient)-386.8(production.)-384.5(There)-389.1(are)-385.7(also)]TJ T* [(safety)-446.6(issues)-445.1(compared)-445.5(with)-449(HAdVs)-445.7(such)-443.1(as)-446.7(the)-442.3(possible)]TJ T* [(occurrance)-310.5(of)-307.4(interspecies)-311.6(adaptation.)-312.1(For)-308.4(example,)-309.7(HAdV-)]TJ 0 -1.1174 TD [(4)-266(i)0(s)-267.1(the)-269.5(only)-269.5(HAdV)-266.2(member)-270.6(of)-267.1(HAdV)-272(E)-267.2(species)-270.1(that)-270.8(is)-267.1(very)]TJ 0 -1.1116 TD [(similar)-425(to)-422.8(SAdVs)-421.6(from)-420.3(that)-426.3(group,)-423.6(indicating)-422.8(its)-423.8(zoonotic)]TJ T* [(origin)-243(and)-246.4(molecular)-245.3(adaptation)-245.3(to)-244.2(its)-245.3(new)-247.2(host)-240.5(\(Purkayastha)]TJ /F7 1 Tf 0 -1.1174 TD [(et)-475.8(al.)]TJ /F4 1 Tf 2.2348 0 TD [(,)-470(2005a;)-474.4(Dehgh)-7.5(an)]TJ /F7 1 Tf 8.0118 0 TD [(et)-475.8(al.)]TJ /F4 1 Tf 2.2348 0 TD [(,)-475.7(2013\).)-475.5(As)-475.2(AdVs)-472.5(have)-479(co-)]TJ -12.4813 -1.1116 TD [(evolved)-246.3(with)-241.7(their)-248.8(hosts)-241.4(\(Benko)]TJ 12.3603 .023 TD ()Tj .6566 -.023 TD [(and)-246.4(Harrach,)-245.8(2003;)-241.8(Davison)]TJ /F7 1 Tf -13.0169 -1.1116 TD [(et)-268.4(al.)]TJ /F4 1 Tf 2.0274 0 TD [(,)-274.1(2003\),)-268.1(there)-272.9(is)-272.8(a)-273(possibility)-271.6(that)-270.8(humans)-273.8(and)-275.2(monkeys)]TJ -2.0274 -1.1174 TD [(could)-490.6(be)-498.7(infected)-496.3(with)-489.3(the)-494.2(same)-497.3(AdVs,)-493.2(a)-497.6(concern)-495(when)]TJ 0 -1.1116 TD [(considering)-400.4(chimpanzee)-404.1(or)-399.6(simian)-400.7(AdV)-396.7(vectors)-401.6(for)-400.7(use)-401.7(in)]TJ T* [(humans.)-496.1(Nevertheless,)-505.8(NHAdV)-504.3(vectors)-499.5(present)-499.5(great)-503.3(po-)]TJ 0 -1.1174 TD [(tential)-298.5(as)-296.9(effective)-297(gene)-300.5(therapy)-298.1(vehicles)-300.4(and)-292.4(will)-299.4(hopefully)]TJ 0 -1.1116 TD [(be)-320.1(part)-322.5(of)-318.9(the)-321.4(successful)-325(AdV)-321.8(vectors)-321(used)-322.2(in)-319.1(the)-321.4(clinics)-327(in)]TJ T* [(the)-332.9(coming)-337.4(years.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 310.8472 416.296 Tm (Acknowledgments)Tj /F4 1 Tf 9.843 0 0 9.843 320.8251 399.855 Tm [(We)-316.7(would)-323.3(like)-322.6(to)-319.1(thank)-323.6(all)-321.5(members)-323.3(of)-319(the)-321.4()50.8(ADVance)47.4()]TJ -1.0137 -1.1116 TD [(international)-594.4(training)-592.1(network)-591.6(\(Adenoviruses)-593.2(as)-590.7(Clinical)]TJ T* [(Treatments;)-283.1(FP7)-279.4(ITN,)-285.2(EU)-280.7(grant)-277.5(agreement)-286.6(ref.)-278.5(290002\))-284.2(and)]TJ 0 -1.1174 TD [(in)-468.9(particular)-469.8(Andrew)-470.3(Baker)-469.6(and)-471(Eric)-467.6(J.)-465.1(Kremer)-471.8(for)-469.8(their)]TJ 0 -1.1116 TD [(advice)-332.8(and)-338.5(encouragement)-338.3(to)-330.6(write)-336.1(this)-338.5(review.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 310.8472 332.107 Tm [(Author)-332.4(Disclosure)-336.7(Statement)]TJ /F4 1 Tf 9.843 0 0 9.843 320.8251 315.666 Tm [(No)-331.4(competing)-336.3(nancial)-334.9(interests)-340.5(exist.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 310.8472 292.3086 Tm (References)Tj /F4 1 Tf 9.2951 0 0 9.2951 310.8472 276.2645 Tm [(Abbink,)-355.7(P.,)-363(Lemckert,)-358.6(A.A.,)-363.5(Ewald,)-355.6(B.A.,)]TJ /F7 1 Tf 17.6878 0 TD [(et)-363.8(al.)]TJ /F4 1 Tf 2.4763 0 TD [(\(2007\).)-359.3(Com-)]TJ -19.2797 -1.1284 TD [(parative)-405.3(seroprevalence)-408.6(and)-401.1(immunogenicity)-409.8(of)-405.2(six)-401.5(rare)-404(se-)]TJ 0 -1.1223 TD [(rotype)-988.8(recombinant)-990.8(adenovirus)-992.7(vaccine)-993.1(vectors)-992.3(from)]TJ 0 -1.1284 TD [(subgroups)-331.2(B)-334.3(and)-334(D.)-337.2(J.)-334.8(Virol.)-332.9(81,)-329.7(46544663.)]TJ -.8844 -1.1223 TD [(Abe,)-378.3(S.,)-381.3(Okuda,)-384.7(K.,)-380(Ura,)-380.7(T.,)]TJ /F7 1 Tf 12.2473 0 TD [(et)-382.1(al.)]TJ /F4 1 Tf 2.519 0 TD [(\(2009\).)-383.7(Adenovirus)-380.2(type)-382.4(5)]TJ -13.8819 -1.1284 TD [(with)-409.7(modied)-415.8(hexons)-406.8(induces)-416.6(robust)-410.4(transgene-specic)-416.6(im-)]TJ 0 -1.1223 TD [(mune)-382.5(responses)-381.4(in)-377.9(mice)-386.1(with)-379.2(pre-existing)-384.2(immunity)-382.8(against)]TJ 0 -1.1284 TD [(adenovirus)-334(type)-333.6(5.)-335.7(J.)-334.8(Gene)-333.8(Med.)-333.3(11,)-335.8(570579.)]TJ -.8844 -1.1223 TD [(Albert,)-428.7(M.L.,)-428.6(Sauter,)-428.7(B.,)-425.9(and)-425.5(Bhardwaj,)-432.5(N.)-428.7(\(1998\).)-426.4(Dendritic)]TJ .8844 -1.1284 TD [(cells)-434(acquire)-442.3(antigen)-435.2(from)-431.7(apoptotic)-441(cells)-434(and)-437.7(induce)-435.7(class)]TJ 0 -1.1223 TD [(I-restricted)-338.2(CTLs.)-331.6(Nature)-342(392,)-329.9(8689.)]TJ -.8844 -1.1284 TD [(Appledorn,)-594.4(D.M.,)-599.1(McBride,)-600.8(A.,)-593.5(Seregin,)-599.7(S.,)]TJ /F7 1 Tf 19.853 0 TD [(et)-595.5(al.)]TJ /F4 1 Tf 2.952 0 TD (\(2008\).)Tj -21.9206 -1.1223 TD [(Complex)-411.5(interactions)-416.1(with)-409.7(several)-410.9(arms)-414.4(of)-411.3(the)-412.7(complement)]TJ 0 -1.1284 TD [(system)-459.7(dictate)-457.2(innate)-459.5(and)-456(humoral)-457.9(immunity)-456(to)-457.2(adenoviral)]TJ 0 -1.1223 TD [(vectors.)-333.6(Gene)-333.8(Ther.)-338.4(15,)-335.8(16061617.)]TJ -.8844 -1.1284 TD [(Arnberg,)-584.8(N.)-581.2(\(2012\).)-585(Adenovirus)-581.4(receptors:)-590(implications)-585.4(for)]TJ .8844 -1.1223 TD [(targeting)-419(of)-417.4(viral)-420.8(vectors.)-419(Trends)-417(Pharmacol.)-426.9(Sci.)-415.7(33,)-415.1(442)]TJ 0 -1.1284 TD (448.)Tj -.8844 -1.1284 TD [(Bailey,)-330.2(A.,)-325.1(and)-327.9(Mautner,)-327.7(V.)-331.2(\(1994\).)-322.7(Phylogenetic)-332.7(relationships)]TJ .8844 -1.1223 TD [(among)-333.9(adenovirus)-334(serotypes.)-339.1(Virology)-333.3(205,)-336(438452.)]TJ -.8844 -1.1284 TD [(Bangari,)-589.4(D.S.,)-590.5(and)-596.3(Mittal,)-587.6(S.K.)-590.4(\(2004\).)-591.1(Porcine)-593.5(adenoviral)]TJ .8844 -1.1223 TD [(vectors)-315.2(evade)-318.3(preexisting)-314.7(humoral)-317.6(immunity)-309.6(to)-316.9(adenoviruses)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(CIRCUMVENTING)-339.9(ANTIVECTOR)-341.1(IMMUNITY)]TJ 53.0113 0 TD (293)Tj ET endstream endobj 28 0 obj <> endobj 29 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 30 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 70.2425 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(and)-285.2(efciently)-285.9(infect)-291(both)-280.6(human)-291.2(and)-285.2(murine)-280.9(cells)-287.7(in)-286.4(culture.)]TJ 0 -1.1223 TD [(Virus)-332.5(Res.)-338(105,)-336(127136.)]TJ -.8844 -1.1284 TD [(Bangari,)-571.1(D.S.,)-566.1(and)-571.9(Mittal,)-569.3(S.K.)-566(\(2005\).)-572.8(Porcine)-569.1(adenovirus)]TJ .8844 -1.1223 TD [(serotype)-522.8(3)-518.6(internalization)-530.2(is)-517.3(independent)-525.4(of)-521(CAR)-523.9(and)-517(al-)]TJ 0 -1.1283 TD [(phavbeta3)-336.6(or)-332(alphavbeta5)-340.5(integrin.)-335.4(Virology)-333.3(332,)-336(157166.)]TJ -.8844 -1.1223 TD [(Bangari,)-424.7(D.S.,)-419.7(and)-419.4(Mittal,)-423(S.K.)-419.7(\(2006\).)-420.3(Development)-429(of)-417.4(non-)]TJ .8844 -1.1284 TD [(human)-474.1(adenoviruses)-471.8(as)-467.1(vaccine)-474.7(vectors.)-473.9(Vaccine)-476.3(24,)-470(849)]TJ 0 -1.1223 TD (862.)Tj -.8844 -1.1284 TD .0115 Tc [(Bang)5.3(ari)11.5(,)-390.7(D.S.,)-378.9(S)2.4(harma,)-378.9(A.)5.3(,)-385(a)1.1(n)5.3(d)-385.1(M)11.5(i)-5.8(ttal)11.5(,)-390.7(S.)5.3(K.)-378.9(\(2)5.3(00)5.3(5a\).)-385(Bo)5.3(vin)5.3(e)]TJ .8844 -1.1223 TD .012 Tc [(aden)5.8(ovi)12(r)-8.3(u)5.8(s)-328.8(t).2(yp)5.8(e)-327.8(3)-329.7(int)12(e)-4.1(rn)5.8(alizati)12(o)-6(n)-329.7(i)12(s)-334.5(i).2(nd)5.8(epend)5.8(e)1.6(nt)-329.1(of)-325.9(prim)12(ary)]TJ 0 -1.1284 TD .0113 Tc [(recep)5.1(t)-.5(ors)-414.9(o)5.1(f)-418.1(h)-1(u)5.1(m)-.6(an)-415.8(aden)5.1(ov)5.1(irus)-414.9(ty)5.1(pe)-413.9(5)-415.8(a).9(nd)-415.8(p)5.1(o)-1(rcine)-413.9(a).9(den)5.1(o)-1(-)]TJ 0 -1.1223 TD .0119 Tc [(vi)11.9(r)-8.4(u)5.7(s)-310.6(t)11.9(y)-6.1(p)-.4(e)-303.5(3)-.4(.)-305.3(B).9(io)5.7(chem.)-305.3(B).9(io)5.7(ph)5.7(ys.)-305.3(R).9(es.)-305.3(C).9(o)5.7(mmu)5.7(n.)-305.3(33)5.7(1,)-305.3(14)5.7(78)]TJ 0 -1.1284 TD .0123 Tc [(14)6.1(84.)]TJ -.8844 -1.1284 TD 0 Tc [(Bangari,)-357.6(D.S.,)-358.7(Shukla,)-355.1(S.,)-350.8(and)-358.4(Mittal,)-355.9(S.K.)-358.7(\(2005b\).)-353.4(Compara-)]TJ .8844 -1.1223 TD [(tive)-406.2(transduction)-406.3(efciencies)-410.1(of)-405.2(human)-407.1(and)-401.1(nonhuman)-407.5(ade-)]TJ 0 -1.1284 TD [(noviral)-244.3(vectors)-248.2(in)-243.7(human,)-242.5(murine,)-244.3(bovine,)-242.5(and)-242.5(porcine)-242.9(cells)-251.1(in)]TJ 0 -1.1223 TD [(culture.)-333.9(Biochem.)-336.5(Biophys.)-333.8(Res.)-338(Commun.)-334.2(327,)-336(960966.)]TJ -.8844 -1.1284 TD [(Barlan,)-442.8(A.U.,)-436.7(Danthi,)-444.7(P.,)-436.2(and)-437.7(Wiethoff,)-440.2(C.M.)-443.6(\(2011a\).)-436.9(Lyso-)]TJ .8844 -1.1223 TD [(somal)-356.8(localization)-363.4(and)-352.3(mechanism)-359.3(of)-356.4(membrane)-356.8(penetration)]TJ 0 -1.1284 TD [(inuence)-479.6(nonenveloped)-483.4(virus)-477.3(activation)-481.4(of)-472.2(the)-479.8(NLRP3)-481.5(in-)]TJ 0 -1.1223 TD [(ammasome.)-338(Virology)-333.3(412,)-336(306314.)]TJ -.8844 -1.1284 TD [(Barlan,)-247.7(A.U.,)-247.6(Grifn,)-247.4(T.M.,)-245.6(McGuire,)-250(K.A.,)-247.6(and)-248.6(Wiethoff,)-245.1(C.M.)]TJ .8844 -1.1223 TD [(\(2011b\).)-652.3(Adenovirus)-648.5(membrane)-655.7(penetration)-649.1(activates)-655.9(the)]TJ 0 -1.1284 TD [(NLRP3)-335.1(inammasome.)-337.7(J.)-334.8(Virol.)-332.9(85,)-335.8(146155.)]TJ -.8844 -1.1223 TD [(Barouch,)-510.7(D.H.,)-509.9(Pau,)-501.6(M.G.,)-507.6(Custers,)-510.2(J.H.,)]TJ /F7 1 Tf 18.0781 0 TD [(et)-510.2(al.)]TJ /F4 1 Tf 2.7752 0 TD [(\(2004\).)-505.7(Im-)]TJ -19.9689 -1.1284 TD [(munogenicity)-270.3(of)-264.9(recombinant)-271.1(adenovirus)-273(serotype)-266.6(35)-268.6(vaccine)]TJ 0 -1.1223 TD [(in)-487.6(the)-485.9(presence)-495.2(of)-484.4(pre-existing)-487.9(anti-Ad5)-490(immunity.)-486.6(J.)-487.3(Im-)]TJ 0 -1.1284 TD [(munol.)-335.3(172,)-329.9(62906297.)]TJ -.8844 -1.1223 TD [(Basner-Tschakarjan,)-301.5(E.,)-288.8(Gaffal,)-289.5(E.,)-294.9(OKeeffe,)-292.3(M.,)]TJ /F7 1 Tf 20.469 0 TD [(et)-290.6(al.)]TJ /F4 1 Tf 2.336 0 TD (\(2006\).)Tj -21.9206 -1.1284 TD [(Adenovirus)-740(efciently)-737.3(transduces)-739.9(plasmacytoid)-743.2(dendritic)]TJ 0 -1.1223 TD [(cells)-324.3(resulting)-328.5(in)-323(TLR9-dependent)-323.8(maturation)-327.2(and)-321.8(IFN-alpha)]TJ 0 -1.1284 TD [(production.)-336.3(J.)-334.8(Gene)-333.8(Med.)-333.3(8,)-335.7(13001306.)]TJ -.8844 -1.1223 TD [(Beard,)-376.2(C.W.,)-375.6(and)-376.7(Spindler,)-369.4(K.R.)-378.9(\(1996\).)-371.5(Analysis)-376.1(of)-374.7(early)-376.8(re-)]TJ .8844 -1.1284 TD [(gion)-481.8(3)-482(mutants)-478.5(of)-484.4(mouse)-479.4(adenovirus)-486.5(type)-479.9(1.)-482.1(J.)-481.2(Virol.)-485.4(70,)]TJ 0 -1.1223 TD (58675874.)Tj -.8844 -1.1284 TD [(Belousova,)-360.8(N.,)-361.7(Mikheeva,)-360.2(G.,)-361.7(Xiong,)-355.6(C.,)]TJ /F7 1 Tf 17.2425 0 TD [(et)-357.7(al.)]TJ /F4 1 Tf 2.4763 0 TD [(\(2010\).)-359.3(Devel-)]TJ -18.8344 -1.1223 TD [(opment)-388.3(of)-386.9(a)-388.6(targeted)-393.1(gene)-387.1(vector)-389.2(platform)-392.7(based)-386.4(on)-390.6(simian)]TJ 0 -1.1284 TD [(adenovirus)-334(serotype)-339.8(24.)-329.7(J.)-334.8(Virol.)-339(84,)-329.7(1008710101.)]TJ -.8844 -1.1223 TD (Benko)Tj 2.2018 .0183 TD ()Tj .4147 -.0183 TD [(,)-494.1(M.,)-493.6(and)-498.7(Harrach,)-501.8(B.)-492.9(\(2003\).)-499.6(Molecular)-496.2(evolution)-497.8(of)]TJ -1.7322 -1.1284 TD [(adenoviruses.)-337.7(Curr.)-333.3(Top.)-337.9(Microbiol.)-334.8(Immunol.)-331.3(272,)-336(335.)]TJ -.8844 -1.1223 TD [(Both,)-261(G.W.)-256.4(\(2004\).)-261.8(Ovine)-256(atadenovirus:)-264.3(a)-254.4(review)-262.7(of)-258.8(its)-260.7(biology,)]TJ .8844 -1.1284 TD [(biosafety)-430.8(prole)-424.5(and)-425.5(application)-432.8(as)-424.5(a)-425.2(gene)-429.8(delivery)-425.5(vector.)]TJ 0 -1.1223 TD [(Immunol.)-337.4(Cell)-331.7(Biol.)-333.6(82,)-335.8(189195.)]TJ -.8844 -1.1284 TD [(Bradley,)-473.5(R.R.,)-467.5(Lynch,)-470.4(D.M.,)-471(Iampietro,)-470.3(M.J.,)]TJ /F7 1 Tf 19.6639 0 TD [(et)-467.5(al.)]TJ /F4 1 Tf 2.6959 0 TD (\(2012a\).)Tj -21.4754 -1.1223 TD [(Adenovirus)-550.9(serotype)-547.2(5)-549.1(neutralizing)-545(antibodies)-550.1(target)-553.3(both)]TJ 0 -1.1284 TD [(hexon)-358.7(and)-364.5(ber)-357.7(following)-363.3(vaccination)-364.4(and)-358.4(natural)-364.4(infection.)]TJ T* [(J.)-334.8(Virol.)-332.9(86,)-335.8(625629.)]TJ -.8844 -1.1223 TD [(Bradley,)-516.2(R.R.,)-510.2(Maxeld,)-511.2(L.F.,)-517.6(Lynch,)-507(D.M.,)]TJ /F7 1 Tf 19.5237 0 TD [(et)-516.3(al.)]TJ /F4 1 Tf 2.7812 0 TD (\(2012b\).)Tj -21.4205 -1.1284 TD [(Adenovirus)-337.5(serotype)-333.7(5-specic)-334.8(neutralizing)-337.6(antibodies)-336.6(target)]TJ 0 -1.1223 TD [(multiple)-515(hexon)-511.2(hypervariable)-510.1(regions.)-512.4(J.)-511.7(Virol.)-509.8(86,)-512.7(1267)]TJ 0 -1.1284 TD (1272.)Tj -.8844 -1.1223 TD [(Bradshaw,)-542(A.C.,)-537.5(Coughlan,)-534.2(L.,)-538.9(Miller,)-535.6(A.M.,)]TJ /F7 1 Tf 19.975 0 TD [(et)-534.5(al.)]TJ /F4 1 Tf 2.83 0 TD (\(2012\).)Tj -21.9206 -1.1284 TD [(Biodistribution)-242.8(and)-242.5(inammatory)-238.9(proles)-240.7(of)-240.5(novel)-242.2(penton)-236.3(and)]TJ 0 -1.1223 TD [(hexon)-535.6(double-mutant)-541.1(serotype)-541.1(5)-530.8(adenoviruses.)-539(J.)-542.2(Control.)]TJ 0 -1.1284 TD [(Release)-338.3(164,)-336(394402.)]TJ -.8844 -1.1223 TD [(Brouwer,)-303(E.,)-307.1(Havenga,)-302(M.J.,)-303.8(Ophorst,)-302.4(O.,)]TJ /F7 1 Tf 17.1937 0 TD [(et)-302.8(al.)]TJ /F4 1 Tf 2.3665 0 TD [(\(2007\).)-298.4(Human)]TJ -18.6759 -1.1284 TD [(adenovirus)-370.6(type)-376.3(35)-366.2(vector)-370.9(for)-371(gene)-374.9(therapy)-371(of)-368.6(brain)-372.6(cancer:)]TJ 0 -1.1223 TD [(improved)-317.7(transduction)-320.9(and)-315.7(bypass)-314.4(of)-313.7(pre-existing)-323.2(anti-vector)]TJ 0 -1.1284 TD [(immunity)-254.7(in)-262(cancer)-257.9(patients.)-257.1(Cancer)-258.5(Gene)-260.6(Ther.)-259.1(14,)-256.5(211219.)]TJ -.8844 -1.1223 TD [(Bru,)-459(T.,)-459.6(Salinas,)-461.7(S.,)-460.6(and)-462.1(Kremer,)-460.4(E.J.)-458.9(\(2010\).)-456.9(An)-459.3(update)-466.2(on)]TJ .8844 -1.1284 TD [(canine)-421.6(adenovirus)-419.4(type)-412.9(2)-421(and)-413.3(its)-419.2(vectors.)-419(Viruses)-415.4(2,)-421.1(2134)]TJ 0 -1.1223 TD (2153.)Tj -.8844 -1.1284 TD [(Bruder,)-240.2(J.T.,)-239.4(Semenova,)-235.9(E.,)-240(Chen,)-235.3(P.,)]TJ /F7 1 Tf 15.1627 0 TD [(et)-235.7(al.)]TJ /F4 1 Tf 2.2323 0 TD [(\(2012\).)-237.4(Modication)]TJ -16.5106 -1.1223 TD [(of)-277.1(Ad5)-282.6(hexon)-279.4(hypervariable)-284.5(regions)-280.5(circumvents)-282.4(pre-existing)]TJ 27.0074 70.8975 TD [(Ad5)-398.5(neutralizing)-398.6(antibodies)-397.6(and)-395(induces)-398.3(protective)-398.9(immune)]TJ 0 -1.1223 TD [(responses.)-338.8(PLoS)-337.6(One)-329.5(7,)-335.7(e33920.)]TJ -.8844 -1.1284 TD [(Calcedo,)-371.7(R.,)-371(Vandenberghe,)-370.2(L.H.,)-369.9(Roy,)-371.3(S.,)]TJ /F7 1 Tf 18.0598 0 TD [(et)-369.9(al.)]TJ /F4 1 Tf 2.4946 0 TD [(\(2009\).)-371.5(Host)]TJ -19.67 -1.1223 TD [(immune)-290.3(responses)-290(to)-286.4(chronic)-291.7(adenovirus)-291.3(infections)-284(in)-292.5(human)]TJ 0 -1.1283 TD [(and)-340.1(nonhuman)-334.3(primates.)-332.8(J.)-334.8(Virol.)-332.9(83,)-335.8(26232631.)]TJ -.8844 -1.1223 TD [(Capone,)-477.7(S.,)-478.9(Meola,)-477.5(A.,)-471.5(Ercole,)-476.5(B.B.,)]TJ /F7 1 Tf 16.2057 0 TD [(et)-473.6(al.)]TJ /F4 1 Tf 2.7081 0 TD [(\(2006\).)-475.2(A)-477.5(novel)]TJ -18.0293 -1.1284 TD [(adenovirus)-395(type)-394.6(6)-390.5(\(Ad6\)-based)-389.7(hepatitis)-396.9(C)-389.2(virus)-391.9(vector)-389.2(that)]TJ 0 -1.1223 TD [(overcomes)-307.7(preexisting)-308.6(anti-ad5)-303.5(immunity)-309.6(and)-303.5(induces)-300.7(potent)]TJ 0 -1.1284 TD [(and)-486.5(broad)-483(cellular)-484(immune)-485.5(responses)-485.1(in)-481.5(rhesus)-481.4(macaques.)]TJ 0 -1.1223 TD [(J.)-334.8(Virol.)-339(80,)-329.7(16881699.)]TJ -.8844 -1.1284 TD [(Carlisle,)-575.3(R.C.,)-571.2(Di,)-568.6(Y.,)-569.1(Cerny,)-573.2(A.M.,)]TJ /F7 1 Tf 16.3947 0 TD [(et)-571.1(al.)]TJ /F4 1 Tf 2.8971 0 TD [(\(2009\).)-572.8(Human)]TJ -18.4075 -1.1223 TD [(erythrocytes)-443.9(bind)-439.1(and)-437.7(inactivate)-442.9(type)-437.3(5)-433.2(adenovirus)-443.8(by)-433.3(pre-)]TJ 0 -1.1284 TD [(senting)-271.6(Coxsackie)-267.3(virus-adenovirus)-271(receptor)-267.9(and)-266.9(complement)]TJ T* [(receptor)-341.1(1.)-329.6(Blood)-334.3(113,)-336(19091918.)]TJ -.8844 -1.1223 TD [(Cauthen,)-257.7(A.N.,)-253.7(Brown,)-253.5(C.C.,)-254(and)-248.6(Spindler,)-253.5(K.R.)-256.9(\(1999\).)]TJ /F7 1 Tf 9.2951 0 0 9.2951 524.466 578.7211 Tm [(In)-252.7(vitro)]TJ /F4 1 Tf -21.8597 -1.1284 TD (and)Tj /F7 1 Tf 1.8908 0 TD [(in)-445(vivo)]TJ /F4 1 Tf 3.3485 0 TD [(characterization)-448.9(of)-441.7(a)-443.5(mouse)-448.9(adenovirus)-443.8(type)-443.4(1)]TJ -5.2392 -1.1223 TD [(early)-340.2(region)-330.1(3)-335.6(null)-334.9(mutant.)-332.9(J.)-334.8(Virol.)-332.9(73,)-335.8(86408646.)]TJ -.8844 -1.1284 TD [(Cerullo,)-505.3(V.,)-502(Seiler,)-507.5(M.P.,)-502.8(Mane,)-502.4(V.,)]TJ /F7 1 Tf 16.0227 0 TD [(et)-504.1(al.)]TJ /F4 1 Tf 2.763 0 TD [(\(2007\).)-505.7(Toll-like)]TJ -17.9013 -1.1223 TD [(receptor)-524.1(9)-524.7(triggers)-520.3(an)-522.9(innate)-520.5(immune)-522.1(response)-522.5(to)-524.2(helper-)]TJ 0 -1.1284 TD [(dependent)-336.6(adenoviral)-338.5(vectors.)-339.7(Mol.)-328.6(Ther.)-338.4(15,)-329.7(378385.)]TJ -.8844 -1.1223 TD [(Charles,)-436(P.C.,)-429(Guida,)-426.9(J.D.,)-428.1(Brosnan,)-432.4(C.F.,)-429(and)-425.5(Horwitz,)-430.5(M.S.)]TJ .8844 -1.1284 TD [(\(1998\).)-395.9(Mouse)-399.8(adenovirus)-395(type-1)-391.1(replication)-398.5(is)-395.3(restricted)-400.3(to)]TJ 0 -1.1223 TD [(vascular)-478.2(endothelium)-477.5(in)-475.4(the)-473.7(CNS)-473.2(of)-478.3(susceptible)-474.3(strains)-474.3(of)]TJ 0 -1.1284 TD [(mice.)-337.4(Virology)-333.3(245,)-336(216228.)]TJ -.8844 -1.1223 TD [(Cheng,)-302.6(C.,)-291.7(Gall,)-298(J.G.,)-300.1(Kong,)-295(W.P.,)]TJ /F7 1 Tf 14.3576 0 TD [(et)-296.7(al.)]TJ /F4 1 Tf 2.3543 0 TD [(\(2007\).)-292.3(Mechanism)-298(of)]TJ -15.8275 -1.1284 TD [(ad5)-431.6(vaccine)-432(immunity)-431.6(and)-425.5(toxicity:)-429.6(ber)-430.9(shaft)-426.6(targeting)-431.2(of)]TJ 0 -1.1223 TD [(dendritic)-339.7(cells.)-336.5(PLoS)-331.5(Pathog.)-336.8(3,)-329.6(e25.)]TJ -.8844 -1.1284 TD [(Cherenova,)-661.5(L.V.,)-650.5(Logunov,)-655.6(D.Y.,)-650.2(Shashkova,)-658.3(E.V.,)]TJ /F7 1 Tf 23.3113 0 TD [(et)-656.5(al.)]TJ /F4 1 Tf -22.4269 -1.1223 TD [(\(2004\).)-316.6(Recombinant)-316.3(avian)-313.5(adenovirus)-315.7(CELO)-309.6(expressing)-314.8(the)]TJ 0 -1.1284 TD [(human)-510.7(interleukin-2:)-512.4(characterization)]TJ /F7 1 Tf 16.1508 0 TD [(in)-512(vitro)]TJ /F4 1 Tf 3.1899 0 TD [(,)-506.3(i)0(n)-505.9(ovo)-512.8(and)]TJ /F7 1 Tf -19.3407 -1.1223 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 2.7934 0 TD [(.)-335.5(Virus)-332.5(Res.)-338(100,)-329.9(257261.)]TJ -3.6778 -1.1284 TD [(Chillon,)-418.9(M.,)-420.4(and)-413.3(Kremer,)-417.7(E.J.)-422.3(\(2001\).)-414.2(Trafcking)-421.3(and)-413.3(propa-)]TJ .8844 -1.1223 TD [(gation)-254(of)-252.7(canine)-250.8(adenovirus)-248.6(vectors)-254.3(lacking)-252.3(a)-248.3(known)-252.4(integrin-)]TJ 0 -1.1284 TD [(interacting)-337.5(motif.)-337(Hum.)-337.1(Gene)-333.8(Ther.)-332.3(12,)-335.8(18151823.)]TJ -.8844 -1.1223 TD [(Cohen,)-296.5(C.J.,)-297.2(Xiang,)-292.7(Z.Q.,)-296.7(Gao,)-293(G.P.,)]TJ /F7 1 Tf 15.1505 0 TD [(et)-290.6(al.)]TJ /F4 1 Tf 2.3482 0 TD [(\(2002\).)-292.3(Chimpanzee)]TJ -16.6143 -1.1284 TD [(adenovirus)-285.2(CV-68)-277.8(adapted)-275.3(as)-278.1(a)-278.8(gene)-283.5(delivery)-279.1(vector)-279.4(interacts)]TJ 0 -1.1223 TD [(with)-568.2(the)-559.1(coxsackievirus)-567.2(and)-565.8(adenovirus)-565.8(receptor.)-560.8(J.)-566.6(Gen.)]TJ 0 -1.1284 TD [(Virol.)-339(83,)-329.7(151155.)]TJ -.8844 -1.1223 TD [(Corredor,)-261.2(J.C.,)-260.6(and)-260.8(Nagy,)-256.5(E.)-264.4(\(2010a\).)-260(A)-257.9(region)-256.9(at)-260.1(the)-260.2(left)-262.1(end)-254.7(of)]TJ .8844 -1.1284 TD [(the)-400.5(fowl)-394.3(adenovirus)-401.1(9)-396.6(genome)-393.1(that)-400.1(is)-395.3(non-essential)]TJ /F7 1 Tf 21.7682 0 TD [(in)-396.2(vitro)]TJ /F4 1 Tf -21.7682 -1.1223 TD [(has)-339.2(consequences)]TJ /F7 1 Tf 7.5143 0 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 2.7873 0 TD [(.)-335.5(J)0(.)-334.8(Gen.)-335.6(Virol.)-332.9(91,)-335.8(5158.)]TJ -11.186 -1.1284 TD [(Corredor,)-255.1(J.C.,)-254.5(and)-254.7(Nagy,)-250.4(E.)-252.2(\(2010b\).)-255.8(The)-250.5(non-essential)-257.3(left)-256(end)]TJ .8844 -1.1223 TD [(region)-250.8(of)-246.6(the)-241.9(fowl)-247.9(adenovirus)-248.6(9)-244.1(genome)-252.8(is)-242.8(suitable)-250.9(for)-242.9(foreign)]TJ 0 -1.1284 TD [(gene)-338.4(insertion/replacement.)-339.3(Virus)-338.6(Res.)-331.9(149,)-336(167174.)]TJ -.8844 -1.1223 TD [(Coughlan,)-418.3(L.,)-416.9(Alba,)-420.6(R.,)-413.7(Parker,)-419.4(A.L.,)]TJ /F7 1 Tf 16.0715 0 TD [(et)-418.7(al.)]TJ /F4 1 Tf 2.5922 0 TD [(\(2010\).)-420.3(Tropism-)]TJ -17.7793 -1.1284 TD [(modication)-358.4(strategies)-360.5(for)-358.8(targeted)-356.5(gene)-356.7(delivery)-358.4(using)-353(ade-)]TJ T* [(noviral)-335.8(vectors.)-339.7(Viruses)-336.1(2,)-329.6(22902355.)]TJ -.8844 -1.1223 TD [(Coughlan,)-558.6(L.,)-557.2(Bradshaw,)-566.4(A.C.,)-555.8(Parker,)-559.7(A.L.,)]TJ /F7 1 Tf 19.9384 0 TD [(et)-552.9(al.)]TJ /F4 1 Tf 2.8727 0 TD (\(2012\).)Tj -21.9267 -1.1284 TD [(Ad5:Ad48)-430.7(hexon)-431.9(hypervariable)-430.9(region)-433.8(substitutions)-429.4(lead)-429.3(to)]TJ 0 -1.1223 TD [(toxicity)-375.1(and)-370.6(increased)-378.8(inammatory)-373.1(responses)-375.3(following)-369.4(in-)]TJ 0 -1.1284 TD [(travenous)-339.9(delivery.)-334.1(Mol.)-334.7(Ther.)-332.3(20,)-335.8(22682281.)]TJ -.8844 -1.1223 TD [(Crawford-Miksza,)-302.8(L.,)-294.9(and)-297.4(Schnurr,)-299.5(D.P.)-291.6(\(1996\).)-298.4(Analysis)-296.8(of)-295.4(15)]TJ .8844 -1.1284 TD [(adenovirus)-364.5(hexon)-352.6(proteins)-359.4(reveals)-362.2(the)-357.8(location)-361.6(and)-352.3(structure)]TJ 0 -1.1223 TD [(of)-447.9(seven)-447.4(hypervariable)-449.2(regions)-445.2(containing)-453.4(serotype-specic)]TJ 0 -1.1284 TD [(residues.)-339(J.)-334.8(Virol.)-332.9(70,)-335.8(18361844.)]TJ -.8844 -1.1223 TD [(Croyle,)-267.9(M.A.,)-263.6(Yu,)-264.2(Q.C.,)-263(and)-260.8(Wilson,)-265.5(J.M.)-261.1(\(2000\).)-267.9(Development)]TJ .8844 -1.1284 TD [(of)-399.1(a)-400.8(rapid)-397(method)-394.4(for)-401.5(the)-394.4(PEGylation)-400.6(of)-399.1(adenoviruses)-398.6(with)]TJ 0 -1.1223 TD [(enhanced)-524.2(transduction)-522.2(and)-517(improved)-525.1(stability)-520.2(under)-519.6(harsh)]TJ 0 -1.1284 TD [(storage)-339.6(conditions.)-332.5(Hum.)-337.1(Gene)-333.8(Ther.)-338.4(11,)-329.7(17131722.)]TJ -.8844 -1.1223 TD [(Davison,)-523.9(A.J.,)-519.6(Benko,)-522.1(M.,)-518(and)-523.1(Harrach,)-520.1(B.)-517.3(\(2003\).)-524(Genetic)]TJ .8844 -1.1284 TD [(content)-526.7(and)-523.1(evolution)-516.1(of)-521(adenoviruses.)-526.8(J.)-523.9(Gen.)-518.6(Virol.)-522(84,)]TJ 0 -1.1223 TD (28952908.)Tj -.8844 -1.1284 TD [(De)-347.6(Ge)18.3(e)14(s)0(t)19.5(,)-353.8(B)13.4(.)0(,)-341.7(S)0(n)21.2(o)0(e)13.8(y)0(s)25(,)-353.8(J)12.9(.)0(,)-341.7(V)0(a)18.3(n)-353.9(Li)22.8(nt)18.6(ho)18(ut)24.7(,)-353.8(S)0(.)21.3(,)]TJ /F7 1 Tf 17.8342 0 TD [(et)-345.5(al)18.6(.)]TJ /F4 1 Tf 2.4336 0 TD [(\(2)21.8(00)18(5\))21.8(.)-353.8(E)0(l)22.8(i)0(m)19(-)]TJ -19.3834 -1.1223 TD [(in)18.6(at)14.4(i)12.6(o)0(n)-286.9(o)0(f)-283.2(i)12.6(nn)18(at)20.5(e)-297.1(i)12.6(mm)18.9(un)18(e)-297.1(r)0(e)23.7(s)0(p)18.9(o)0(n)18(s)0(e)20.8(s)-298.1(an)19.9(d)-292.9(l)0(i)19.2(v)0(e)19.9(r)-295.2(in)18.6(a)17(m)12.5(m)12.5(a)0(t)14.4(i)12.6(on)-286.9(by)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (294)Tj 43.6471 0 TD [(LOPEZ-GORDO)-336.9(ET)-338.7(AL.)]TJ ET endstream endobj 31 0 obj <> endobj 32 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 33 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 67.9748 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(PE)19.3(Gy)16.4(l)12.6(a)0(t)14.4(i)12.6(on)-585.8(of)-588.1(a)14(d)0(e)13.8(n)0(o)24.1(v)0(i)18.6(r)0(a)17.6(l)-597.3(ve)19.9(ct)20.5(or)21.8(s)-597(a)0(n)19.9(d)-597.9(m)12.5(e)0(t)14.4(h)0(y)24.1(l)0(p)18.6(r)0(e)17.6(d)0(n)18(i)12.6(so)18.9(l)12.6(o)0(n)18(e)0(.)]TJ 0 -1.1223 TD [(Hu)16.4(m)12.5(.)-323.3(Ge)18.3(ne)-315.6(Th)16.1(e)14(r)0(.)-313.6(1)0(6)18(,)-323.3(14)18(39)24.1(1)18(45)18(1.)]TJ -.8844 -1.1284 TD [(Dehghan,)-401.4(S.,)-393.5(Seto,)-397.5(J.,)-402(Liu,)-392.2(E.B.,)]TJ /F7 1 Tf 13.888 0 TD [(et)-400.4(al.)]TJ /F4 1 Tf 2.5556 0 TD [(\(2013\).)-395.9(Computational)]TJ -15.5591 -1.1223 TD [(analysis)-421.4(of)-423.5(four)-420(human)-419.3(adenovirus)-419.4(type)-419(4)-421(genomes)-422.9(reveals)]TJ 0 -1.1283 TD [(molecular)-380.6(evolution)-375.8(through)-374.8(two)-373.5(interspecies)-383.3(recombination)]TJ 0 -1.1223 TD [(events.)-337.3(Virology)-333.3(443,)-336(197207.)]TJ -.8844 -1.1284 TD [(Di)-397.7(Paolo,)-397.7(N.C.,)-397.2(Miao,)-400(E.A.,)-400.4(Iwakura,)-400(Y.,)]TJ /F7 1 Tf 17.639 0 TD [(et)-400.4(al.)]TJ /F4 1 Tf 2.5556 0 TD [(\(2009\).)-395.9(Virus)]TJ -19.3102 -1.1223 TD [(binding)-280.4(to)-274.2(a)-272.7(plasma)-275.8(membrane)-283.6(receptor)-274(triggers)-276.3(interleukin-1)]TJ 0 -1.1284 TD [(alpha-mediated)-1176(proinammatory)-1168.7(macrophage)-1166.8(response)]TJ /F7 1 Tf 0 -1.1223 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 2.7934 0 TD [(.)-335.5(Immunity)-330.8(31,)-335.8(110121.)]TJ -3.6778 -1.1284 TD [(Doszpoly,)-487.4(A.,)-477.6(Wellehan,)-486.7(J.F.,)-478.3(Childress,)-479.4(A.L.,)]TJ /F7 1 Tf 20.0909 0 TD [(et)-479.7(al.)]TJ /F4 1 Tf 2.7203 0 TD (\(2013\).)Tj -21.9268 -1.1223 TD [(Partial)-372.8(characterization)-381.8(of)-368.6(a)-370.3(new)-372.2(adenovirus)-370.6(lineage)-378.4(discov-)]TJ 0 -1.1284 TD [(ered)-340.7(in)-329.1(testudinoid)-338.1(turtles.)-334.4(Infect.)-336.7(Genet.)-333.5(Evol.)-337.4(17,)-329.7(106112.)]TJ -.8844 -1.1284 TD [(Dudley,)-341.6(R.W.,)-332.9(Lu,)-337.7(Y.,)-337.3(Gilbert,)-336.8(R.,)]TJ /F7 1 Tf 14.4186 0 TD [(et)-333.3(al.)]TJ /F4 1 Tf 2.4275 0 TD [(\(2004\).)-334.9(Sustained)-339.9(im-)]TJ -15.9617 -1.1223 TD [(provement)-614.9(of)-612.5(muscle)-611.2(function)-610.4(one)-608.5(year)-615.1(after)-610.9(full-length)]TJ 0 -1.1284 TD [(dystrophin)-392.1(gene)-387.1(transfer)-393.2(into)-389.8(mdx)-390.4(mice)-392.2(by)-384.5(a)-388.6(gutted)-394.3(helper-)]TJ 0 -1.1223 TD [(dependent)-318.3(adenoviral)-320.2(vector.)-316.1(Hum.)-318.8(Gene)-315.5(Ther.)-320.1(15,)-311.4(145156.)]TJ -.8844 -1.1284 TD [(Ehrhardt,)-328.6(A.,)-319(and)-321.8(Kay,)-323.5(M.A.)-324.5(\(2002\).)-322.7(A)-318.9(new)-323.4(adenoviral)-326.3(helper-)]TJ .8844 -1.1223 TD [(dependent)-464.7(vector)-456.3(results)-462.1(in)-457.2(long-term)-459.9(therapeutic)-464.3(levels)-458.6(of)]TJ 0 -1.1284 TD [(human)-321.7(coagulation)-317.5(factor)-324.4(IX)-315.2(at)-321.1(low)-318.6(doses)]TJ /F7 1 Tf 17.4865 0 TD [(in)-316.9(vivo)]TJ /F4 1 Tf 2.7751 0 TD [(.)-317.2(Blood)-316(99,)]TJ -20.2617 -1.1223 TD (39233930.)Tj -.8844 -1.1284 TD [(Ersching,)-477.8(J.,)-469(Hernandez,)-479.6(M.I.,)-471.7(Cezarotto,)-477.4(F.S.,)]TJ /F7 1 Tf 20.1031 0 TD [(et)-473.6(al.)]TJ /F4 1 Tf 2.7081 0 TD (\(2010\).)Tj -21.9268 -1.1223 TD [(Neutralizing)-302.6(antibodies)-293.9(to)-292.5(human)-291.2(and)-297.4(simian)-295.4(adenoviruses)-294.9(in)]TJ 0 -1.1284 TD [(humans)-339.2(and)-334(New-World)-334.2(monkeys.)-333.3(Virology)-339.4(407,)-329.9(16.)]TJ -.8844 -1.1223 TD [(Eto,)-538.6(Y.,)-538.6(Yoshioka,)-536.2(Y.,)-538.6(Ishida,)-536.6(T.,)]TJ /F7 1 Tf 15.1993 0 TD [(et)-540.6(al.)]TJ /F4 1 Tf 2.8361 0 TD [(\(2010\).)-536.2(Optimized)]TJ -17.151 -1.1284 TD [(PEGylated)-271.1(adenovirus)-273(vector)-267.2(reduces)-271.2(the)-266.3(anti-vector)-273.3(humoral)]TJ 0 -1.1223 TD [(immune)-503.8(response)-504.2(against)-501.4(adenovirus)-504.8(and)-504.8(induces)-502(a)-504.5(thera-)]TJ 0 -1.1284 TD [(peutic)-526.6(effect)-529.9(against)-525.8(metastatic)-527(lung)-524.5(cancer.)-526.3(Biol.)-522.7(Pharm.)]TJ 0 -1.1223 TD [(Bull.)-339.7(33,)-329.7(15401544.)]TJ -.8844 -1.1284 TD [(Farina,)-306.8(S.F.,)-299.1(Gao,)-299.1(G.P.,)-297.7(Xiang,)-304.9(Z.Q.,)]TJ /F7 1 Tf 15.181 0 TD [(et)-302.8(al.)]TJ /F4 1 Tf 2.3604 0 TD [(\(2001\).)-298.4(Replication-)]TJ -16.657 -1.1223 TD [(defective)-312.1(vector)-316(based)-307.1(on)-311.3(a)-309.3(chimpanzee)-308.1(adenovirus.)-315.8(J.)-304.3(Virol.)]TJ 0 -1.1284 TD [(75,)-335.8(1160311613.)]TJ -.8844 -1.1223 TD [(Fernandes,)-579.5(P.,)-576.5(Peixoto,)-574.3(C.,)-572.3(Santiago,)-578.6(V.M.,)]TJ /F7 1 Tf 19.4566 0 TD [(et)-571.1(al.)]TJ /F4 1 Tf 2.9032 0 TD (\(2013a\).)Tj -21.4754 -1.1284 TD [(Bioprocess)-240.3(development)-238.3(for)-236.8(canine)-238.6(adenovirus)-236.4(type)-236(2)-231.9(vectors.)]TJ 0 -1.1223 TD [(Gene)-339.9(Ther.)-332.3(20,)-335.8(353360.)]TJ -.8844 -1.1284 TD [(Fernandes,)-335.5(P.,)-326.4(Santiago,)-334.7(V.M.,)-330.7(Rodrigues,)-328.4(A.F.,)]TJ /F7 1 Tf 19.8896 0 TD [(et)-333.3(al.)]TJ /F4 1 Tf 2.4214 0 TD (\(2013b\).)Tj -21.4266 -1.1223 TD [(Impact)-468(of)-466.1(E1)-465.7(and)-462.1(Cre)-469.2(on)-463.8(adenovirus)-468.2(vector)-462.4(amplication:)]TJ 0 -1.1284 TD [(developing)-691.8(MDCK)-684.8(CAV-2-E1)-686.5(and)-687.8(E1-Cre)-687.3(transcomple-)]TJ 0 -1.1223 TD [(menting)-339.1(cell)-331.1(lines.)-338.4(PLoS)-331.5(One)-335.6(8,)-335.7(e60342.)]TJ -.8844 -1.1284 TD (Franc)Tj 1.8969 0 TD [()-51.3(ois,)-413.8(A.,)-404.4(Eterradossi,)-416.2(N.,)-404.4(Delmas,)-411.6(B.,)]TJ /F7 1 Tf 15.9251 0 TD [(et)-412.6(al.)]TJ /F4 1 Tf 2.58 0 TD [(\(2001\).)-408.1(Con-)]TJ -19.5175 -1.1223 TD [(struction)-499.3(of)-490.5(avian)-496.5(adenovirus)-498.7(CELO)-492.5(recombinants)-502.2(in)-493.7(cos-)]TJ 0 -1.1284 TD [(mids.)-334.2(J.)-334.8(Virol.)-332.9(75,)-335.8(52885301.)]TJ -.8844 -1.1223 TD [(Gall,)-334.6(J.,)-334.9(Kass-Eisler,)-337.6(A.,)-337.3(Leinwand,)-335.8(L.,)-331.5(and)-334(Falck-Pedersen,)-337.1(E.)]TJ .8844 -1.1284 TD [(\(1996\).)-450.8(Adenovirus)-453.3(type)-449.4(5)-451.5(and)-449.9(7)-451.5(capsid)-453.1(chimera:)-453.7(ber)-449.1(re-)]TJ 0 -1.1223 TD [(placement)-400.8(alters)-393.8(receptor)-402.1(tropism)-391.2(without)-397.3(affecting)-395.6(primary)]TJ 0 -1.1284 TD [(immune)-339.1(neutralization)-335.5(epitopes.)-337(J.)-334.8(Virol.)-332.9(70,)-335.8(21162123.)]TJ -.8844 -1.1284 TD [(Gall,)-371.2(J.G.,)-373.3(Crystal,)-370.2(R.G.,)-372.8(and)-370.6(Falck-Pedersen,)-373.7(E.)-368.1(\(1998\).)-371.5(Con-)]TJ .8844 -1.1223 TD [(struction)-724.9(and)-718.2(characterization)-723.3(of)-722.3(hexon-chimeric)-717.2(adeno-)]TJ 0 -1.1284 TD [(viruses:)-511(specication)-506.8(of)-502.7(adenovirus)-510.9(serotype.)-504.5(J.)-505.6(Virol.)-503.7(72,)]TJ 0 -1.1223 TD (1026010264.)Tj -.8844 -1.1284 TD [(Gao,)-530.8(W.,)-529.2(Robbins,)-529(P.D.,)-523.4(and)-529.2(Gambotto,)-530(A.)-526.3(\(2003\).)-530.1(Human)]TJ .8844 -1.1223 TD [(adenovirus)-449.9(type)-443.4(35:)-439(nucleotide)-451.5(sequence)-444(and)-443.8(vector)-444.1(devel-)]TJ 0 -1.1284 TD [(opment.)-339.6(Gene)-333.8(Ther.)-332.3(10,)-335.8(19411949.)]TJ -.8844 -1.1223 TD [(Garnett,)-335.5(C.T.,)-330.4(Erdman,)-332.2(D.,)-331.2(Xu,)-331.3(W.,)-334(and)-334(Gooding,)-331.5(L.R.)-330.4(\(2002\).)]TJ .8844 -1.1284 TD [(Prevalence)-313.8(and)-309.6(quantitation)-306.1(of)-307.6(species)-310.2(C)-309.9(adenovirus)-309.6(DNA)-310.1(in)]TJ 0 -1.1223 TD [(human)-333.9(mucosal)-336.9(lymphocytes.)-337(J.)-334.8(Virol.)-332.9(76,)-335.8(1060810616.)]TJ -.8844 -1.1284 TD [(Gattoni,)-334.5(A.,)-331.2(Parlato,)-336.8(A.,)-331.2(Vangieri,)-335.7(B.,)]TJ /F7 1 Tf 15.7116 0 TD [(et)-333.3(al.)]TJ /F4 1 Tf 2.4214 0 TD [(\(2006\).)-334.9(Interferon-)]TJ -17.2486 -1.1223 TD [(gamma:)-300.6(biologic)-302.5(functions)-298.6(and)-297.4(HCV)-295(therapy)-303.9(\(type)-299.4(I/II\))-296.1(\(1)-295.4(of)]TJ 0 -1.1284 TD [(2)-335.6(parts\).)-337.7(Clin.)-333.6(Ther.)-332.3(157,)-336(377386.)]TJ -.8844 -1.1223 TD .012 Tc [(Geis)12(b)-5.7(e)1.6(rt,)-469.9(T)-2.2(.)5.8(W)1.4(.,)-469.9(Bail)12(ey,)-469.9(M).4(.)5.8(,)-469.9(Hens)12(ley,)-469.9(L.,)]TJ /F7 1 Tf 18.0476 0 TD .0114 Tc [(et)-470(al)11.4(.)]TJ /F4 1 Tf 2.7508 0 TD .012 Tc [(\(2)5.8(01)5.8(1\).)-469.9(R)1(e-)]TJ -19.914 -1.1284 TD .0106 Tc [(combinant)-245.1(a).2(denovi)10.6(r)-9.7(u)4.4(s)-244.8(s)-.8(erot)]TJ 11.3141 0 TD .0098 Tc [(ype)-244.6(2)3.6(6)-246.5(\()1.2(Ad26\))-242.7(and)-246.5(A)-4.1(d35)-240.4(v)-2.5(accine)]TJ -11.3141 -1.1223 TD .012 Tc [(vecto)5.8(r)-2.7(s)-554.5(byp)5.8(ass)-560.6(i).2(m)12(m)-5.7(un)5.8(ity)-555.4(to)-555.4(Ad)5.8(5)-561.5(a)1.6(nd)-555.4(prot)12(ect)-560.9(n)-.3(o)5.8(nhu)5.8(man)]TJ 0 -1.1284 TD .0116 Tc [(primates)-426.8(agai)11.6(n)-6.4(s).2(t)-427.1(e)1.2(bo)5.4(lavi)11.6(r)-8.7(u)5.4(s)-432.9(c)1.2(h)5.4(a)1.2(lleng)5.4(e.)-427.6(J.)-427.6(Vi)11.6(r)-8.7(o)5.4(l.)-427.6(85)5.4(,)-427.6(422)5.4(2)]TJ 0 -1.1223 TD .0123 Tc [(423)6.1(3.)]TJ 26.1291 70.8975 TD 0 Tc [(Ginsberg,)-355.5(H.S.)-346.5(\(1996\).)-353.2(The)-354.2(ups)-353.3(and)-352.3(downs)-349.1(of)-350.3(adenovirus)-358.4(vec-)]TJ .8844 -1.1223 TD [(tors.)-330.9(Bull.)-333.6(NY)-338.9(Acad.)-333.9(Med.)-333.3(73,)-335.8(5358.)]TJ -.8844 -1.1284 TD [(Greber,)-381.5(U.F.)-383.1(\(2002\).)-377.6(Signalling)-384.4(in)-377.9(viral)-384.3(entry.)-378.8(Cell.)-386.6(Mol.)-377.4(Life)]TJ .8844 -1.1223 TD [(Sci.)-330.3(59,)-335.8(608626.)]TJ -.8844 -1.1283 TD [(Green,)-318.1(N.K.,)-320.8(Herbert,)-320.1(C.W.,)-320.7(Hale,)-321.1(S.J.,)]TJ /F7 1 Tf 16.3032 0 TD [(et)-315(al.)]TJ /F4 1 Tf 2.3909 0 TD [(\(2004\).)-322.8(Extended)]TJ -17.8098 -1.1223 TD [(plasma)-416(circulation)-422.9(time)-418(and)-413.3(decreased)-426.3(toxicity)-417.8(of)-411.3(polymer-)]TJ 9.2951 0 0 9.2951 319.0676 662.3998 Tm [(coated)-336.2(adenovirus.)-334.1(Gene)-333.8(Ther.)-338.4(11,)-329.7(12561263.)]TJ -.8844 -1.1223 TD [(Greenall,)-455.7(S.A.,)-456.3(Tyack,)-456.4(S.G.,)-456.3(Johnson,)-456.8(M.A.,)-458.8(and)-456(Sapats,)-456(S.I.)]TJ .8844 -1.1284 TD [(\(2010\).)-322.8(Antibody)-324.9(fragments,)-323.6(expressed)-325.5(by)-323.5(a)-321.5(fowl)-327.2(adenovirus)]TJ 0 -1.1223 TD [(vector,)-358.8(are)-364.9(able)-356.1(to)-359.6(neutralize)-366.5(infectious)-363.3(bursal)-359.7(disease)-358.9(virus.)]TJ 0 -1.1284 TD [(Avian)-335.3(Pathol.)-330.2(39,)-335.8(339348.)]TJ -.8844 -1.1223 TD [(Haisma,)-393.3(H.J.,)-391.6(Boesjes,)-396.2(M.,)-389.9(Beerens,)-392(A.M.,)]TJ /F7 1 Tf 18.0903 0 TD [(et)-394.3(al.)]TJ /F4 1 Tf 2.5434 0 TD [(\(2009\).)-389.8(Sca-)]TJ -19.7493 -1.1284 TD [(venger)-255.6(receptor)-255.7(A:)-257.5(a)-254.4(new)-256.3(route)-256.7(for)-255.1(adenovirus)-260.8(5.)-256.4(Mol.)-255.4(Pharm.)]TJ T* [(6,)-329.6(366374.)]TJ -.8844 -1.1223 TD [(Hammond,)-256.1(J.M.,)-255.1(and)-254.7(Johnson,)-255.5(M.A.)-251.4(\(2005\).)-255.7(Porcine)-258(adenovirus)]TJ .8844 -1.1284 TD [(as)-424.5(a)-425.2(delivery)-425.5(system)-429.2(for)-419.8(swine)-425.9(vaccines)-431.3(and)-425.5(immunothera-)]TJ 0 -1.1223 TD [(peutics.)-336.8(Vet.)-335.1(J.)-328.7(169,)-336(1727.)]TJ -.8844 -1.1284 TD [(Havenga,)-234.9(M.J.,)-236.8(Lemckert,)-236.6(A.A.,)-235.4(Grimbergen,)-234.7(J.M.,)]TJ /F7 1 Tf 20.6398 0 TD [(et)-235.7(al.)]TJ /F4 1 Tf 2.2262 0 TD [(\(2)21.8(00)18(1\))21.8(.)]TJ -21.9816 -1.1223 TD [(Im)22.2(pr)15.7(ov)24.1(ed)-437.5(ad)13.8(e)14(n)0(o)18(v)0(i)18.6(r)0(u)21.8(s)-450.6(ve)19.9(ct)20.5(or)21.8(s)-450.6(f)0(o)21.8(r)-447.7(in)18.6(fe)17.6(ct)20.5(io)18.6(n)-445.4(o)0(f)-441.7(c)0(a)21.8(r)0(d)15.7(i)12.6(ov)18(as)20.8(cu)19.9(la)14.4(r)]TJ 0 -1.1284 TD [(t)12.6(i)0(s)19.5(s)0(u)18.9(e)0(s)14.7(.)-323.3(J)12.9(.)-323.3(Vi)17(ro)21.8(l.)-316.8(75)24.1(,)-323.3(3)0(3)18(3)0(5)18()0(3)24.1(3)0(4)18(2)0(.)]TJ -.8844 -1.1223 TD .0116 Tc [(Haviv)5.4(,)-616.7(Y.S.)5.4(,)-616.7(B).6(l)11.6(a)-4.5(ck)5.4(wel)11.6(l)-5.8(,)-610.6(J).1(.L.,)-610.6(Kan)5.4(e)1.2(rv)5.4(a,)-616.7(A.,)]TJ /F7 1 Tf 19.7066 0 TD .0097 Tc [(et)-618.1(al.)]TJ /F4 1 Tf 3.0374 0 TD .0125 Tc [(\(2)6.3(00)6.3(2\).)]TJ -21.8596 -1.1284 TD .0103 Tc [(Adenovi)10.3(r)-10(al)-355.2(gene)-353.9(therapy)-355.8(f)1.7(or)-352(renal)-355.2(cancer)-352(re)-6.2(quires)-354.9(retarget-)]TJ 0 -1.1223 TD [(ing)-343.7(t)10.2(o)-349.4(a)-.2(lt)10.2(e)-12(r)1.6(native)-341.8(cel)10.2(l)-7.2(u)-2.1(lar)-339.9(r)1.6(eceptors)10.2(.)-349(C)-.8(anc)-6.3(e)-.2(r)-339.9(R)-.8(es.)-337.5(6)-2.1(2,)-343.6(4273)]TJ 0 -1.1284 TD .0123 Tc [(4)6.1(281)6.1(.)]TJ -.8844 -1.1223 TD 0 Tc [(Hofherr,)-446.9(S.E.,)-450.5(Shashkova,)-451(E.V.,)-449.2(Weaver,)-453.3(E.A.,)]TJ /F7 1 Tf 20.1458 0 TD [(et)-449.2(al.)]TJ /F4 1 Tf 2.6593 0 TD (\(2008\).)Tj -21.9206 -1.1284 TD [(Modication)-370.3(of)-368.6(adenoviral)-375.1(vectors)-370.1(with)-373.1(polyethylene)-372.5(glycol)]TJ 0 -1.1223 TD (modulates)Tj /F7 1 Tf 4.5134 0 TD [(in)-390.1(vivo)]TJ /F4 1 Tf 3.2387 0 TD [(tissue)-392.5(tropism)-391.2(and)-388.9(gene)-393.2(expression.)-394.2(Mol.)]TJ -7.7521 -1.1284 TD [(Ther.)-332.3(16,)-335.8(12761282.)]TJ -.8844 -1.1223 TD [(Hofmann,)-374.7(C.,)-371(Lo)]TJ 6.6421 .0183 TD ()Tj .4147 -.0183 TD [(ser,)-372.1(P.,)-375.2(Cichon,)-369.2(G.,)]TJ /F7 1 Tf 8.3194 0 TD [(et)-376(al.)]TJ /F4 1 Tf 2.5068 0 TD [(\(1999\).)-371.5(Ovine)-378(ade-)]TJ -16.9986 -1.1284 TD [(novirus)-654.5(vectors)-656.8(overcome)-662.2(preexisting)-656.2(humoral)-659.2(immunity)]TJ 0 -1.1223 TD [(against)-294.1(human)-291.2(adenoviruses)]TJ /F7 1 Tf 11.6739 0 TD [(in)-292.5(vivo)]TJ /F4 1 Tf 2.7508 0 TD [(.)-292.8(J)0(.)-286(Virol.)-296.3(73,)-293.1(69306936.)]TJ -15.3091 -1.1284 TD [(Holterman,)-475.7(L.,)-471.8(Vogels,)-468.8(R.,)-474.7(van)-474.3(der)-470.5(Vlugt,)-470.9(R.,)]TJ /F7 1 Tf 20.1031 0 TD [(et)-473.6(al.)]TJ /F4 1 Tf 2.702 0 TD (\(2004\).)Tj -21.9206 -1.1223 TD [(Novel)-518.3(replication-incompetent)-528.9(vector)-517.3(derived)-523.5(from)-517.1(adeno-)]TJ 0 -1.1284 TD [(virus)-367.5(type)-364.1(11)-366.2(\(Ad11\))-366.9(for)-364.9(vaccination)-370.5(and)-364.5(gene)-368.8(therapy:)-364.5(low)]TJ 0 -1.1223 TD [(seroprevalence)-439.1(and)-431.6(non-cross-reactivity)-439.7(with)-440.2(Ad5.)-429(J.)-438.5(Virol.)]TJ 0 -1.1284 TD [(78,)-329.7(1320713215.)]TJ -.8844 -1.1223 TD [(Ibanes,)-352.3(S.,)-350.8(and)-352.3(Kremer,)-356.7(E.J.)-349.1(\(2013\).)-353.2(Canine)-355.1(adenovirus)-352.3(type)-351.9(2)]TJ .8844 -1.1284 TD [(vector)-438(generation)-442.2(via)-437.1(I-Sce1-mediated)-440.1(intracellular)-441.3(genome)]TJ 0 -1.1223 TD [(release.)-335.9(PLoS)-331.5(One)-335.6(8,)-335.7(e71032.)]TJ -.8844 -1.1284 TD [(Jankovic,)-337.6(D.,)-337.3(Liu,)-337.3(Z.,)-337.6(and)-334(Gause,)-339.3(W.C.)-338.9(\(2001\).)-334.9(Th1-)-334.1(and)-340.1(Th2-)]TJ .8844 -1.1223 TD [(cell)-550.7(commitment)-555.8(during)-551.5(infectious)-558.5(disease:)-553.7(asymmetry)-552.6(in)]TJ 0 -1.1284 TD [(divergent)-334.2(pathways.)-339.1(Trends)-331.7(Immunol.)-337.4(22,)-329.7(450457.)]TJ -.8844 -1.1223 TD [(Jian,)-357.2(L.,)-355.9(Zhao,)-360.5(Q.,)-355.6(Zhang,)-360.7(S.,)]TJ /F7 1 Tf 12.5156 0 TD [(et)-357.7(al.)]TJ /F4 1 Tf 2.4702 0 TD [(\(2013\).)-359.3(The)-354.2(prevalence)-365.8(of)]TJ -14.1014 -1.1284 TD [(neutralising)-332.6(antibodies)-336.6(to)-329.1(chimpanzee)-338.6(adenovirus)-334(type)-333.6(6)-329.5(and)]TJ 0 -1.1223 TD [(type)-565.3(7)-561.3(i)0(n)-566.9(healthy)-569.4(adult)-564.9(volunteers,)-565.3(patients)-568.1(with)-568.2(chronic)]TJ 0 -1.1284 TD [(hepatitis)-464(B)-468.5(and)-462.1(patients)-464.4(with)-464.5(primary)-466.3(hepatocellular)-474.4(carci-)]TJ T* [(noma)-315.4(in)-310.8(China.)-314.2(Arch.)-319.8(Virol.)-314.6(DOI)-317(10.1007/s00705-013-1828-)]TJ 0 -1.1223 TD [(y.)-329.6([Epub)-334.3(ahead)-336.6(of)-338.1(print])]TJ -.8844 -1.1284 TD [(Jones,)-363.1(M.S.,)-362.5(Harrach,)-367.6(B.,)-364.9(Ganac,)-368.8(R.D.,)]TJ /F7 1 Tf 16.4252 0 TD [(et)-363.8(al.)]TJ /F4 1 Tf 2.4885 0 TD [(\(2007\).)-365.4(New)-361.5(ad-)]TJ -18.0293 -1.1223 TD [(enovirus)-433.2(species)-432.1(found)-436.1(in)-432.8(a)-431.3(patient)-434.7(presenting)-431(with)-434(gastro-)]TJ 0 -1.1284 TD [(enteritis.)-338.3(J.)-328.7(Virol.)-339(81,)-329.7(59785984.)]TJ -.8844 -1.1223 TD [(Kajon,)-536.6(A.E.,)-534.6(Brown,)-534(C.C.,)-534.6(and)-541.4(Spindler,)-534(K.R.)-537.4(\(1998\).)-530.1(Dis-)]TJ .8844 -1.1284 TD [(tribution)-306.3(of)-301.5(mouse)-308.6(adenovirus)-303.5(type)-309.2(1)-305.1(i)0(n)-298.6(intraperitoneally)-313.3(and)]TJ 0 -1.1223 TD [(intranasally)-361.2(infected)-368.7(adult)-357.5(outbred)-360.7(mice.)-361.8(J.)-365.3(Virol.)-357.3(72,)-360.2(1219)]TJ 0 -1.1284 TD (1223.)Tj -.8844 -1.1223 TD [(Kanerva,)-548.2(A.,)-550.8(Mikheeva,)-549.3(G.V.,)-552.6(Krasnykh,)-545.2(V.,)]TJ /F7 1 Tf 19.9506 0 TD [(et)-546.7(al.)]TJ /F4 1 Tf 2.8544 0 TD (\(2002\).)Tj -21.9206 -1.1284 TD [(Targeting)-525.1(adenovirus)-523.1(to)-524.2(the)-528.6(serotype)-522.8(3)-524.7(receptor)-524.1(increases)]TJ 0 -1.1223 TD [(gene)-326.2(transfer)-326.1(efciency)-327.7(to)-323(ovarian)-328.3(cancer)-325(cells.)-330.4(Clin.)-321.4(Cancer)]TJ 0 -1.1284 TD [(Res.)-331.9(8,)-335.7(275280.)]TJ -.8844 -1.1223 TD [(Kass-Eisler,)-569.4(A.,)-569.1(Leinwand,)-573.7(L.,)-569.4(Gall,)-566.4(J.,)]TJ /F7 1 Tf 17.7244 0 TD [(et)-571.1(al.)]TJ /F4 1 Tf 2.8971 0 TD [(\(1996\).)-572.8(Cir-)]TJ -19.7371 -1.1284 TD [(cumventing)-575.5(the)-577.4(immune)-577(response)-583.5(to)-573(adenovirus-mediated)]TJ 0 -1.1223 TD [(gene)-332.3(therapy.)-334.5(Gene)-339.9(Ther.)-332.3(3,)-335.7(154162.)]TJ -.8844 -1.1284 TD [(Katze,)-386.5(M.G.,)-379.5(He,)-384.3(Y.,)-380(and)-382.8(Gale,)-388.2(M.)-383.7(\(2002\).)-377.6(Viruses)-384.9(and)-382.8(inter-)]TJ .8844 -1.1223 TD [(feron:)-271.4(a)-266.6(ght)-265.2(for)-273.4(supremacy.)-271.2(Nat.)-268(Rev.)-271.8(Immunol.)-270.4(2,)-268.6(675687.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(CIRCUMVENTING)-339.9(ANTIVECTOR)-341.1(IMMUNITY)]TJ 53.0113 0 TD (295)Tj ET endstream endobj 34 0 obj <> endobj 35 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 36 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 62.022 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(Khare,)-574.2(R.,)-572.3(Reddy,)-570.9(V.S.,)-566.1(Nemerow,)-575.7(G.R.,)-568(and)-571.9(Barry,)-575.6(M.A.)]TJ .8844 -1.1223 TD [(\(2012\).)-292.3(Identication)-298(of)-295.4(adenovirus)-291.3(serotype)-297.1(5)-292.9(hexon)-291.6(regions)]TJ 0 -1.1284 TD [(that)-479.4(interact)-484(with)-482.8(scavenger)-483.1(receptors.)-486.8(J.)-481.2(Virol.)-479.3(86,)-482.2(2293)]TJ 0 -1.1223 TD (2301.)Tj -.8844 -1.1283 TD [(Khatri,)-349.5(A.,)-349.5(Xu,)-343.5(Z.Z.,)-351.9(and)-346.2(Both,)-346.4(G.W.)-347.9(\(1997\).)-347.1(Gene)-352.1(expression)]TJ .8844 -1.1223 TD [(by)-585.8(atypical)-585.4(recombinant)-582.2(ovine)-583.8(adenovirus)-590.2(vectors)-583.6(during)]TJ 0 -1.1284 TD [(abortive)-370.6(infection)-364.1(of)-368.6(human)-364.4(and)-364.5(animal)-373.7(cells)]TJ /F7 1 Tf 19.0174 0 TD [(in)-365.7(vitro)]TJ /F4 1 Tf 3.0435 0 TD [(.)-359.9(Viro-)]TJ -22.0609 -1.1223 TD [(logy)-335.5(239,)-329.9(226237.)]TJ -.8844 -1.1284 TD [(Klonjkowski,)-404.8(B.,)-395.4(Gilardi-Hebenstreit,)-409.7(P.,)-399.6(Hadchouel,)-405.4(J.,)]TJ /F7 1 Tf 23.5613 0 TD [(et)-406.5(al.)]TJ /F4 1 Tf -22.677 -1.1223 TD [(\(1997\).)-408.1(A)-410.4(recombinant)-411.4(E1-deleted)-413.6(canine)-415.5(adenoviral)-411.7(vector)]TJ 0 -1.1284 TD [(capable)-547.9(of)-539.3(transduction)-546.6(and)-547.5(expression)-540.5(of)-545.4(a)-541.1(transgene)-551.5(in)]TJ 0 -1.1223 TD [(human-derived)-341.4(cells)-336.5(and)]TJ /F7 1 Tf 10.3687 0 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 2.7934 0 TD [(.)-329.4(Hum.)-337.1(Gene)-333.8(Ther.)-338.4(8,)-335.7(2103)]TJ -13.1621 -1.1284 TD (2115.)Tj -.8844 -1.1284 TD [(Kochanek,)-344.8(S.,)-344.7(Clemens,)-341.8(P.R.,)-343.6(Mitani,)-344.2(K.,)]TJ /F7 1 Tf 17.2913 0 TD [(et)-345.5(al.)]TJ /F4 1 Tf 2.4458 0 TD [(\(1996\).)-341(A)-343.3(new)]TJ -18.8527 -1.1223 TD [(adenoviral)-350.7(vector:)-346.1(replacement)-346.6(of)-350.3(all)-345(viral)-347.7(coding)-346.1(sequences)]TJ 0 -1.1284 TD [(with)-275.5(28)-165(kb)-274.7(of)-271(DNA)-279.6(independently)-275.1(expressing)-278.2(both)-274.5(full-length)]TJ 0 -1.1223 TD [(dystrophin)-593.4(and)-590.2(beta-galactosidase.)-597.6(Proc.)-589.5(Natl.)-590.8(Acad.)-596.2(Sci.)]TJ 0 -1.1284 TD [(USA)-335.8(93,)-329.7(57315736.)]TJ -.8844 -1.1223 TD [(Kremer,)-429.9(E.J.,)-428.5(Boutin,)-431.5(S.,)-424(Chillon,)-431.1(M.,)-426.5(and)-431.6(Danos,)-426.5(O.)-428.7(\(2000\).)]TJ .8844 -1.1284 TD [(Canine)-556.3(adenovirus)-559.7(vectors:)-558.8(an)-553.4(alternative)-561.3(for)-554(adenovirus-)]TJ 0 -1.1223 TD [(mediated)-335.5(gene)-338.3(transfer.)-332.3(J.)-334.8(Virol.)-339(74,)-329.7(505512.)]TJ -.8844 -1.1284 TD (Ku)Tj .8051 .0122 TD ()Tj .4147 -.0122 TD [(min,)-243.5(D.,)-245.8(Hofmann,)-246.6(C.,)-249(Rudolph,)-243.2(M.,)]TJ /F7 1 Tf 14.7845 0 TD [(et)-247.9(al.)]TJ /F4 1 Tf 2.2506 0 TD [(\(2002\).)-243.5(Biology)-248.6(of)]TJ -17.3706 -1.1223 TD [(ovine)-413(adenovirus)-413.3(infection)-412.9(of)-411.3(nonpermissive)-411.8(cells.)-415.8(J.)-408(Virol.)]TJ 0 -1.1284 TD [(76,)-335.8(1088210893.)]TJ -.8844 -1.1223 TD [(Kuriyama,)-366.3(S.,)-363(Tominaga,)-370.4(K.,)-361.7(Kikukawa,)-372.1(M.,)]TJ /F7 1 Tf 18.7856 0 TD [(et)-369.9(al.)]TJ /F4 1 Tf 2.4885 0 TD [(\(1998\).)-365.4(In-)]TJ -20.3897 -1.1284 TD [(hibitory)-355.5(effects)-364.5(of)-356.4(human)-358.3(sera)-358.1(on)-354(adenovirus-mediated)-367(gene)]TJ 0 -1.1223 TD [(transfer)-338.3(into)-334.9(rat)-329.6(liver.)-335.5(Anticancer)-338.2(Res.)-338(18,)-335.8(23452351.)]TJ -.8844 -1.1284 TD [(Lau,)-579.9(A.A.,)-577(Rozaklis,)-579.6(T.,)-581.6(Ibanes,)-578(S.,)]TJ /F7 1 Tf 16.2545 0 TD [(et)-577.2(al.)]TJ /F4 1 Tf 2.9154 0 TD [(\(2012\).)-578.9(Helper-)]TJ -18.2855 -1.1223 TD [(dependent)-409.8(canine)-409.4(adenovirus)-413.3(vector-mediated)-416.1(transgene)-411.2(ex-)]TJ 0 -1.1284 TD [(pression)-395.7(in)-396.2(a)-400.8(neurodegenerative)-397.2(lysosomal)-398.6(storage)-400.6(disorder.)]TJ 0 -1.1223 TD [(Gene)-333.8(491,)-336(5357.)]TJ -.8844 -1.1284 TD [(Laver,)-348.9(W.G.,)-348(Younghusband,)-354.4(H.B.,)-348.4(and)-346.2(Wrigley,)-352.4(N.G.)-345.1(\(1971\).)]TJ .8844 -1.1223 TD [(Purication)-516.5(and)-517(properties)-518.7(of)-521(chick)-514.8(embryo)-519.3(lethal)-519.9(orphan)]TJ 0 -1.1284 TD [(virus)-337(\(an)-330.2(avian)-337.9(adenovirus\).)-336.5(Virology)-333.3(45,)-335.8(598614.)]TJ -.8844 -1.1223 TD [(Leen,)-279.3(A.M.,)-281.9(Sili,)-276.3(U.,)-276.3(Vanin,)-280.5(E.F.,)]TJ /F7 1 Tf 13.7599 0 TD [(et)-278.4(al.)]TJ /F4 1 Tf 2.3177 0 TD [(\(2004\).)-274(Conserved)-284.3(CTL)]TJ -15.1932 -1.1284 TD [(epitopes)-428.4(on)-421.1(the)-424.9(adenovirus)-425.5(hexon)-425.8(protein)-427.2(expand)-424(subgroup)]TJ 0 -1.1223 TD [(cross-reactive)-472.3(and)-462.1(subgroup-specic)-465.4(CD8)]TJ /F9 1 Tf 17.578 0 TD (+)Tj /F4 1 Tf 1.1772 0 TD [(T)-465.6(cells.)-464.6(Blood)]TJ -18.7551 -1.1284 TD [(104,)-336(24322440.)]TJ -.8844 -1.1223 TD [(Lemckert,)-358.6(A.A.,)-357.4(Grimbergen,)-356.7(J.,)-359.3(Smits,)-355(S.,)]TJ /F7 1 Tf 17.9805 0 TD [(et)-357.7(al.)]TJ /F4 1 Tf 2.4702 0 TD [(\(2006\).)-359.3(Gen-)]TJ -19.5663 -1.1284 TD [(eration)-364.4(of)-368.6(a)-364.2(novel)-364.2(replication-incompetent)-370.3(adenoviral)-369(vector)]TJ 0 -1.1223 TD [(derived)-535.7(from)-535.4(human)-529(adenovirus)-535.3(type)-534.8(49:)-530.5(manufacture)-540.5(on)]TJ 0 -1.1284 TD [(PER.C6)-253(cells,)-251.1(tropism)-244.8(and)-248.6(immunogenicity.)-251.3(J.)-249.4(Gen.)-250.3(Virol.)-253.6(87,)]TJ 0 -1.1223 TD (28912899.)Tj -.8844 -1.1284 TD [(Lenaerts,)-510.6(L.,)-502.3(Verbeken,)-505.7(E.,)-508.4(De)-506.2(Clercq,)-503.8(E.,)-508.4(and)-504.8(Naesens,)-507.6(L.)]TJ .8844 -1.1223 TD [(\(2005\).)-310.5(Mouse)-308.3(adenovirus)-309.6(type)-309.2(1)-305.1(infection)-309.2(in)-310.8(SCID)-311(mice:)-306.4(an)]TJ 0 -1.1284 TD [(experimental)-360.3(model)-351.6(for)-358.8(antiviral)-351.3(therapy)-358.8(of)-356.4(systemic)-353.9(adeno-)]TJ T* [(virus)-410.2(infections.)-418.3(Antimicrob.)-410(Agents)-413.8(Chemother.)-412.4(49,)-415.1(4689)]TJ 0 -1.1223 TD (4699.)Tj -.8844 -1.1284 TD [(Le)18(na)19.9(er)17.6(t)12.6(s)0(,)-328.7(L)0(.)16.2(,)-335.5(Da)18.3(el)20.5(em)14.2(a)14(n)0(s)18.9(,)-341.6(D.)22.6(,)-341.6(G)0(e)18.3(u)0(k)24.1(e)0(n)19.9(s)0(,)-328.7(N)0(.)16.5(,)]TJ /F7 1 Tf 17.4438 0 TD [(et)-327.2(al)18.6(.)]TJ /F4 1 Tf 2.4092 0 TD [(\(2)21.8(00)18(6\))21.8(.)-335.5(M)0(o)18.8(u)0(s)18.9(e)]TJ -18.9686 -1.1223 TD [(ad)19.9(en)19.9(ov)18(ir)16.3(us)-219(t)12.6(y)0(p)18(e)-230(1)-231.9(a)0(t)20.5(t)0(a)20.5(c)0(h)13.8(m)12.5(en)19.9(t)-231.3(i)12.6(s)-231(n)0(o)18(t)-231.3(m)12.5(e)0(d)19.9(i)0(a)14.4(t)12.6(ed)-224.1(by)-219.9(t)12.6(h)0(e)-224.1(c)0(o)19.9(x)0(s)18.9(a)0(c)21.8(k)0(i)18.6(e)0(-)]TJ 0 -1.1284 TD [(ad)19.9(en)19.9(ov)18(ir)16.3(us)-310.5(re)17.6(ce)21.8(pt)18.6(or)15.7(.)-323.3(F)0(E)19.3(B)13.4(S)-326.3(L)0(e)18(t)12.6(t.)-316.8(58)24.1(0,)-317.4(39)24.1(37)18(3)18(94)24.1(2.)]TJ -.8844 -1.1223 TD [(Lenaerts,)-400.9(L.,)-398.6(McVey,)-400.4(J.H.,)-397.6(Baker,)-394.5(A.H.,)]TJ /F7 1 Tf 17.1388 0 TD [(et)-400.4(al.)]TJ /F4 1 Tf 2.5556 0 TD [(\(2009\).)-395.9(Mouse)]TJ -18.81 -1.1284 TD [(adenovirus)-492.6(type)-492.1(1)-488.1(and)-486.5(human)-492.4(adenovirus)-492.6(type)-492.1(5)-488.1(differ)-493.3(in)]TJ 0 -1.1223 TD [(endothelial)-274.2(cell)-264(tropism)-269.2(and)-266.9(liver)-268.4(targeting.)-272.7(J.)-267.7(Gene.)-266.8(Med.)-272.3(11,)]TJ 0 -1.1284 TD (119127.)Tj -.8844 -1.1223 TD .012 Tc [(Len)5.8(aert)12(s)-5.1(,)-494.3(L)-2.2(.)5.8(,)-500.4(v)5.8(a)1.6(n)-500.5(D)4.2(am,)-494.3(W)1.4(.,)-494.3(Perso)5.8(ons)12(,)-505.8(L)3.9(.,)-494.3(and)-494.4(N)4.2(aes)12(e)-3.8(ns,)-494.3(L)-2.2(.)]TJ .8844 -1.1284 TD .0115 Tc [(\(201)5.3(2\).)-439.9(I)2.9(nt)11.5(eract)11.5(i)-5.9(o)-.8(n)-433.9(b)-.8(etween)-440(mo)5.3(use)-438.1(a)1.1(d)5.3(e)1.1(nov)5.3(irus)-439.1(t)11.5(y)-6.5(p)5.3(e)-438.1(1)-440(a)1.1(nd)]TJ 0 -1.1223 TD .0104 Tc [(cell)-519.8(s)-1(urface)-524.6(heparan)-520.4(s)-1(ulfate)-524.6(proteoglycans.)-520.3(PLoS)-517.2(One)-524.6(7)-1.9(,)]TJ 0 -1.1284 TD .0119 Tc [(e31)5.7(454)5.7(.)]TJ -.8844 -1.1223 TD 0 Tc [(Li,)-507.9(X.,)-502(Bangari,)-510.1(D.S.,)-505.1(Sharma,)-502.1(A.,)-508.1(and)-504.8(Mittal,)-502.2(S.K.)-505(\(2009\).)]TJ .8844 -1.1284 TD [(Bovine)-295.9(adenovirus)-297.4(serotype)-297.1(3)-292.9(utilizes)-293(sialic)-299.4(acid)-295.1(as)-296.4(a)-291(cellular)]TJ 0 -1.1223 TD [(receptor)-335(for)-334.4(virus)-337(entry.)-336.1(Virology)-333.3(392,)-329.9(162168.)]TJ -.8844 -1.1284 TD [(Liu,)-483.7(Q.,)-477.6(White,)-484(L.R.,)-476.8(Clark,)-487.3(S.A.,)]TJ /F7 1 Tf 14.9858 0 TD [(et)-479.7(al.)]TJ /F4 1 Tf 2.7142 0 TD [(\(2005\).)-481.3(Akt/protein)]TJ -16.8156 -1.1223 TD [(kinase)-587.2(B)-590.4(activation)-591.2(by)-585.8(adenovirus)-590.2(vectors)-589.7(contributes)-595.3(to)]TJ 27.0074 70.8975 TD [(NFkappaB-dependent)-730(CXCL10)-721.4(expression.)-723.5(J.)-719(Virol.)-723.3(79,)]TJ 0 -1.1223 TD (1450714515.)Tj -.8844 -1.1284 TD [(Lockett,)-437.2(L.J.,)-428.5(and)-431.6(Both,)-431.8(G.W.)-433.3(\(2002\).)-432.5(Complementation)-431.2(of)-435.7(a)]TJ .8844 -1.1223 TD [(defective)-495(human)-492.4(adenovirus)-492.6(by)-488.2(an)-486.3(otherwise)-493.4(incompatible)]TJ 0 -1.1283 TD [(ovine)-583.8(adenovirus)-590.2(recombinant)-582.2(carrying)-587(a)-583.8(functional)-583.8(E1A)]TJ 0 -1.1223 TD [(gene.)-338.4(Virology)-333.3(294,)-336(333341.)]TJ -.8844 -1.1284 TD [(Logunov,)-661.7(D.Y.,)-662.4(Ilyinskaya,)-662.8(G.V.,)-662.4(Cherenova,)-661.5(L.V.,)]TJ /F7 1 Tf 23.3052 0 TD [(et)-662.6(al.)]TJ /F4 1 Tf -22.4208 -1.1223 TD [(\(2004\).)-694.8(Restoration)-697.6(of)-697.9(p53)-689.6(tumor-suppressor)-701.4(activity)-696.5(in)]TJ 0 -1.1284 TD [(human)-315.6(tumor)-313.1(cells)]TJ /F7 1 Tf 7.9107 0 TD [(in)-310.8(vitro)]TJ /F4 1 Tf 9.2951 0 0 9.2951 425.4802 641.4802 Tm [(and)-309.6(in)-316.9(their)-311.1(xenografts)]TJ /F7 1 Tf 9.5514 0 TD [(in)-310.8(vivo)]TJ /F4 1 Tf 3.0801 0 TD (by)Tj -23.8419 -1.1223 TD [(recombinant)-515.1(avian)-508.7(adenovirus)-504.8(CELO-p53.)-513.8(Gene)-504.6(Ther.)-509.2(11,)]TJ 0 -1.1284 TD (7984.)Tj -.8844 -1.1223 TD (Lo)Tj .7014 .0183 TD ()Tj .4147 -.0183 TD [(ser,)-451.4(P.,)-454.5(Hillgenberg,)-451.4(M.,)-450.9(Arnold,)-455.6(W.,)]TJ /F7 1 Tf 16.1325 0 TD [(et)-455.3(al.)]TJ /F4 1 Tf 2.6654 0 TD [(\(2000\).)-450.8(Ovine)]TJ -19.0296 -1.1284 TD [(adenovirus)-327.9(vectors)-327.5(mediate)-323.1(efcient)-328.9(gene)-320.1(transfer)-326.1(to)-323(skeletal)]TJ T* [(muscle.)-336.8(Gene)-339.9(Ther.)-332.3(7,)-335.7(14911498.)]TJ -.8844 -1.1223 TD (Lo)Tj .7014 .0183 TD ()Tj .4147 -.0183 TD [(ser,)-250.1(P.,)-247.2(Hofmann,)-246.6(C.,)-249(Both,)-248.8(G.W.,)]TJ /F7 1 Tf 13.766 0 TD [(et)-247.9(al.)]TJ /F4 1 Tf 2.2567 0 TD [(\(2003\).)-243.5(Construction,)]TJ -16.2545 -1.1284 TD [(rescue,)-466.3(and)-468.2(characterization)-467.2(of)-460(vectors)-467.7(derived)-462.5(from)-468.3(ovine)]TJ 0 -1.1223 TD [(atadenovirus.)-338(J.)-334.8(Virol.)-332.9(77,)-335.8(1194111951.)]TJ -.8844 -1.1284 TD [(Lukashev,)-285.1(A.N.,)-278.1(Ivanova,)-280.2(O.E.,)-278.4(Eremeeva,)-284.1(T.P.,)-279.8(and)-279.1(Iggo,)-277.4(R.D.)]TJ .8844 -1.1223 TD [(\(2008\).)-463(Evidence)-460.3(of)-460(frequent)-458.9(recombination)-459.9(among)-462(human)]TJ 0 -1.1284 TD [(adenoviruses.)-337.7(J.)-334.8(Gen.)-335.6(Virol.)-332.9(89,)-335.8(380388.)]TJ -.8844 -1.1223 TD [(Mack,)-526.8(C.A.,)-519.2(Song,)-515.9(W.R.,)-522(Carpenter,)-523(H.,)]TJ /F7 1 Tf 17.8769 0 TD [(et)-522.4(al.)]TJ /F4 1 Tf 2.7995 0 TD [(\(1997\).)-517.9(Cir-)]TJ -19.792 -1.1284 TD [(cumvention)-343.8(of)-344.2(anti-adenovirus)-340.1(neutralizing)-343.7(immunity)-340.1(by)-341.8(ad-)]TJ 0 -1.1223 TD [(ministration)-327.3(of)-319.8(an)-321.7(adenoviral)-320.2(vector)-322.1(of)-319.8(an)-321.7(alternate)-323.7(serotype.)]TJ 0 -1.1284 TD [(Hum.)-337.1(Gene)-333.8(Ther.)-338.4(8,)-329.6(99109.)]TJ -.8844 -1.1223 TD [(Maione,)-422.8(D.,)-416.6(Della)-412.1(Rocca,)-420.8(C.,)-413.7(Giannetti,)-423.8(P.,)]TJ /F7 1 Tf 18.5844 0 TD [(et)-418.7(al.)]TJ /F4 1 Tf 2.5922 0 TD [(\(2001\).)-414.2(An)]TJ -20.2922 -1.1284 TD [(improved)-403.1(helper-dependent)-405(adenoviral)-405.6(vector)-401.4(allows)-401.1(persis-)]TJ 0 -1.1223 TD [(tent)-424.5(gene)-417.6(expression)-424.6(after)-421.8(intramuscular)-424.8(delivery)-419.4(and)-419.4(over-)]TJ 0 -1.1284 TD [(comes)-300.6(preexisting)-296.4(immunity)-297.4(to)-292.5(adenovirus.)-297.5(Proc.)-296.7(Natl.)-292(Acad.)]TJ 0 -1.1223 TD [(Sci.)-336.4(USA)-335.8(98,)-335.8(59865991.)]TJ -.8844 -1.1284 TD [(Martiniello-Wilks,)-526.6(R.,)-517.4(Dane,)-523(A.,)-514.2(Voeks,)-524.1(D.J.,)]TJ /F7 1 Tf 20.0116 0 TD [(et)-522.3(al.)]TJ /F4 1 Tf 2.7995 0 TD (\(2004\).)Tj -21.9267 -1.1223 TD [(Gene-directed)-308.6(enzyme)-305.8(prodrug)-298.4(therapy)-303.9(for)-297.8(prostate)-302.6(cancer)-306.7(in)]TJ 0 -1.1284 TD [(a)-345.9(mouse)-345.2(model)-345.5(that)-345.2(imitates)-347.5(the)-345.6(development)-342(of)-344.2(human)-346.1(dis-)]TJ 0 -1.1223 TD [(ease.)-341.7(J.)-328.7(Gene)-339.9(Med.)-333.3(6,)-335.7(4354.)]TJ -.8844 -1.1284 TD [(Mastrangeli,)-440.2(A.,)-428.8(Harvey,)-434.1(B.G.,)-427.7(Yao,)-433.2(J.,)]TJ /F7 1 Tf 16.9803 0 TD [(et)-430.9(al.)]TJ /F4 1 Tf 2.6227 0 TD [(\(1996\).)-426.4()52.4(Sero-)]TJ -18.7185 -1.1223 TD [(switch)47.8()-392.8(adenovirus-mediated)]TJ /F7 1 Tf 12.4363 0 TD [(in)-396.2(vivo)]TJ /F4 1 Tf 3.2509 0 TD [(gene)-399.3(transfer:)-398.9(circum-)]TJ -15.6872 -1.1284 TD [(vention)-309(of)-307.6(anti-adenovirus)-309.6(humoral)-305.4(immune)-308.6(defenses)-307.1(against)]TJ 0 -1.1223 TD [(repeat)-362.9(adenovirus)-358.4(vector)-352.6(administration)-362.3(by)-354(changing)-356.7(the)-357.8(ad-)]TJ 0 -1.1284 TD [(enovirus)-335.6(serotype.)-339.9(Hum.)-331(Gene)-339.9(Ther.)-332.3(7,)-335.7(7987.)]TJ -.8844 -1.1223 TD [(McVey,)-540.7(D.,)-538.6(Zuber,)-539.8(M.,)-542.4(Ettyreddy,)-539.3(D.,)]TJ /F7 1 Tf 17.1572 0 TD [(et)-534.6(al.)]TJ /F4 1 Tf 2.8361 0 TD [(\(2010\).)-536.2(Char-)]TJ -19.1089 -1.1284 TD [(acterization)-352.2(of)-350.3(human)-346.1(adenovirus)-346.2(35)-347.9(and)-346.2(derivation)-352(of)-344.2(com-)]TJ 0 -1.1223 TD [(plex)-339.7(vectors.)-333.6(Virol.)-332.9(J.)-334.8(7,)-335.7(276.)]TJ -.8844 -1.1284 TD [(Michou,)-290.5(A.I.,)-285(Lehrmann,)-287.9(H.,)-282.4(Saltik,)-286.9(M.,)-286.2(and)-285.2(Cotten,)-283.2(M.)-286.1(\(1999\).)]TJ .8844 -1.1223 TD [(Mutational)-470.4(analysis)-470.2(of)-466.2(the)-467.6(avian)-466(adenovirus)-468.2(CELO,)-468.2(which)]TJ 0 -1.1284 TD [(provides)-274.6(a)-272.7(basis)-270.9(for)-267.3(gene)-271.3(delivery)-273(vectors.)-272.6(J.)-267.7(Virol.)-271.9(73,)-268.7(1399)]TJ 0 -1.1223 TD (1410.)Tj -.8844 -1.1284 TD [(Mittal,)-246.1(S.K.,)-242.9(Prevec,)-238.4(L.,)-246.1(Graham,)-238.5(F.L.,)-243.2(and)-242.5(Babiuk,)-241.1(L.A.)-241.8(\(1995\).)]TJ .8844 -1.1284 TD [(Development)-276.5(of)-277.1(a)-272.7(bovine)-272.9(adenovirus)-273(type)-272.6(3-based)-273.1(expression)]TJ 0 -1.1223 TD [(vector.)-340.5(J.)-334.8(Gen.)-329.6(Virol.)-339(76)-329.6(\(Pt)-334.4(1\),)-332(93102.)]TJ -.8844 -1.1284 TD [(Mok,)-402.3(H.,)-404.4(Palmer,)-403.9(D.J.,)-397.7(Ng,)-404.5(P.,)-399.6(and)-401.1(Barry,)-404.8(M.A.)-397.7(\(2005\).)-402(Eva-)]TJ .8844 -1.1223 TD [(luation)-253.6(of)-246.6(polyethylene)-250.5(glycol)-247.9(modication)-254.7(of)-246.6(rst-generation)]TJ 0 -1.1284 TD [(and)-565.8(helper-dependent)-569.7(adenoviral)-564.2(vectors)-565.3(to)-560.8(reduce)-564.7(innate)]TJ 0 -1.1223 TD [(immune)-339.1(responses.)-332.7(Mol.)-334.6(Ther.)-338.4(11,)-329.7(6679.)]TJ -.8844 -1.1284 TD [(Morrison,)-302.5(J.,)-292.2(Briggs,)-299.4(S.S.,)-293(Green,)-299.8(N.,)]TJ /F7 1 Tf 15.3213 0 TD [(et)-296.7(al.)]TJ /F4 1 Tf 2.3482 0 TD [(\(2008\).)-298.4(Virotherapy)]TJ -16.7851 -1.1223 TD [(of)-716.2(ovarian)-712.6(cancer)-721.4(with)-714.6(polymer-cloaked)-717.4(adenovirus)-712.1(re-)]TJ 0 -1.1284 TD [(targeted)-356.5(to)-347.4(the)-351.7(epidermal)-350.1(growth)-351.8(factor)-348.8(receptor.)-353.4(Mol.)-346.9(Ther.)]TJ 0 -1.1223 TD [(16,)-335.8(244251.)]TJ -.8844 -1.1284 TD [(Morrison,)-241.5(J.,)-237.3(Briggs,)-238.4(S.S.,)-238.1(Green,)-238.8(N.K.,)]TJ /F7 1 Tf 15.9312 0 TD [(et)-241.8(al.)]TJ /F4 1 Tf 2.2384 0 TD [(\(2009\).)-237.4(Cetuximab)]TJ -17.2852 -1.1223 TD [(retargeting)-523.4(of)-514.9(adenovirus)-517(via)-510.3(the)-516.4(epidermal)-520.9(growth)-516.5(factor)]TJ 0 -1.1284 TD [(receptor)-255.7(for)-249(treatment)-252(of)-252.7(intraperitoneal)-252.6(ovarian)-255.1(cancer.)-251.9(Hum.)]TJ 0 -1.1223 TD [(Gene)-339.9(Ther.)-332.3(20,)-335.8(239251.)]TJ -.8844 -1.1284 TD .023 Tc [(Mu)4.6(ru)4.6(ve)6.5(,)-458.9(D)3(.)4.6(A)3(.,)-452.8(Pe)]TJ 7.4045 .0427 TD 0 Tc ()Tj .4025 -.0427 TD .0188 Tc [(tri)-5.2(lli)-5.2(,)-463.1(V)-1.2(.,)-463.1(Zai)-5.2(s)1.2(s)-4.9(,)-457(A.)-5.7(K.,)]TJ /F7 1 Tf 10.021 0 TD .0219 Tc [(et)-453.4(al.)]TJ /F4 1 Tf 2.7813 0 TD .0196 Tc [(\(2008)-4.9(\).)-456.2(Th)-4.9(e)]TJ -19.7249 -1.1223 TD .0191 Tc [(i)-4.9(n).7(ammaso)-5.4(me)-631.8(reco)-5.4(gni)-4.9(zes)-632.8(c)2.6(y)-5.4(t)]TJ 13.1682 0 TD .0186 Tc [(os)-5.1(oli)-5.4(c)-632.3(mi)-5.4(crob)-5.9(ial)-627.5(a)-4(nd)-634.2(hos)-5(t)]TJ -13.1682 -1.1284 TD .0196 Tc [(D)-6.5(N)-.4(A)-293.2(a)3.1(nd)-291.6(t)-4.4(r)-1.2(igg)-4.9(e)3.1(rs)-290.7(an)-291.6(in)-4.9(nate)-289.7(i)-4.4(m)1.6(m)-4.5(une)-289.7(res)-4.1(pons)-4.1(e.)-285.4(N)-6.5(a)3.1(t)-4.4(u)1.2(re)-289.7(4)-4.9(52,)]TJ 0 -1.1223 TD .0184 Tc [(1)-6.1(031)-6.1(07.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm 0 Tc (296)Tj 43.6471 0 TD [(LOPEZ-GORDO)-336.9(ET)-338.7(AL.)]TJ ET endstream endobj 37 0 obj <> endobj 38 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 39 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 59.7543 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(Myhre,)-439.6(S.,)-430.1(Henning,)-439.4(P.,)-430.1(Granio,)-435.4(O.,)]TJ /F7 1 Tf 15.5713 0 TD [(et)-437(al.)]TJ /F4 1 Tf 2.6288 0 TD [(\(2007\).)-432.5(Decreased)]TJ -17.3157 -1.1223 TD [(immune)-369.6(reactivity)-367.8(towards)-367.5(a)-370.3(knobless,)-369.1(afbody-targeted)-369.4(ad-)]TJ 0 -1.1284 TD [(enovirus)-335.6(type)-333.6(5)-335.6(vector.)-334.4(Gene)-339.9(Ther.)-332.3(14,)-335.8(376381.)]TJ -.8844 -1.1223 TD [(Nan,)-238.1(X.,)-233.6(Peng,)-239.5(B.,)-230.7(Hahn,)-238.2(T.W.,)]TJ /F7 1 Tf 12.6925 0 TD [(et)-235.7(al.)]TJ /F4 1 Tf 2.2262 0 TD [(\(2003\).)-237.4(Development)-233.8(of)-234.4(an)]TJ -14.0343 -1.1283 TD [(Ad7)-1136.5(cosmid)-1131.5(system)-1136.8(and)-1133(generation)-1131.4(of)-1131(an)-1132.8(Ad7-)]TJ 0 -1.1223 TD [(deltaE1deltaE3HIV\()-95.8(MN\))-540.3(env/rev)-547.9(recombinant)-545.6(virus.)-544.5(Gene)]TJ 0 -1.1284 TD [(Ther.)-338.4(10,)-329.7(326336.)]TJ -.8844 -1.1223 TD [(Nguyen,)-397.1(T.,)-392.5(Nery,)-393(J.,)-389.8(Joseph,)-393.7(S.,)]TJ /F7 1 Tf 14.0343 0 TD [(et)-394.3(al.)]TJ /F4 1 Tf 2.5434 0 TD [(\(1999\).)-395.9(Mouse)-387.6(adeno-)]TJ -15.6933 -1.1284 TD [(virus)-239.5(\()-81.7(MAV-1\))-239.7(expression)-241.6(in)-237.6(primary)-234.5(human)-236.3(endothelial)-243.7(cells)]TJ 0 -1.1223 TD [(and)-248.6(generation)-253.1(of)-252.7(a)-248.3(full-length)-252.1(infectious)-247.4(plasmid.)-252.9(Gene)-248.4(Ther.)]TJ 0 -1.1284 TD [(6,)-335.7(12911297.)]TJ -.8844 -1.1223 TD [(Ni,)-349(S.,)-350.8(Bernt,)-347(K.,)-349.5(Gaggar,)-354.8(A.,)]TJ /F7 1 Tf 12.5095 0 TD [(et)-345.5(al.)]TJ /F4 1 Tf 2.4519 0 TD [(\(2005\).)-353.2(Evaluation)-345.5(of)-350.3(bio-)]TJ -14.077 -1.1284 TD [(distribution)-244.3(and)-236.4(safety)-241.9(of)-240.5(adenovirus)-242.5(vectors)-242.1(containing)-239.9(group)]TJ T* [(B)-303.8(bers)-302(after)-299.9(intravenous)-303.1(injection)-306.3(into)-298.3(baboons.)-303.3(Hum.)-300.5(Gene)]TJ 0 -1.1223 TD [(Ther.)-338.4(16,)-329.7(664677.)]TJ -.8844 -1.1284 TD [(Nicol,)-328.7(C.G.,)-330.1(Graham,)-330(D.,)-325.1(Miller,)-328.3(W.H.,)]TJ /F7 1 Tf 16.4496 0 TD [(et)-327.2(al.)]TJ /F4 1 Tf 2.4153 0 TD [(\(2004\).)-328.8(Effect)-326.3(of)]TJ -17.9805 -1.1223 TD [(adenovirus)-590.2(serotype)-583.8(5)-579.6(ber)-589.4(and)-584.1(penton)-583.9(modications)-583.3(on)]TJ /F7 1 Tf 0 -1.1284 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 3.1289 0 TD [(tropism)-330.2(in)-335.2(rats.)-335.1(Mol.)-334.7(Ther.)-338.4(10,)-329.7(344354.)]TJ -4.0133 -1.1223 TD [(Ojkic,)-353.1(D.,)-349.5(and)-352.3(Nagy,)-354.1(E.)-349.8(\(2001\).)-347.1(The)-354.2(long)-347.7(repeat)-356.8(region)-348.4(is)-352.6(dis-)]TJ .8844 -1.1284 TD [(pensable)-445.4(for)-444.2(fowl)-443(adenovirus)-443.8(replication)]TJ /F7 1 Tf 17.4194 0 TD [(in)-438.9(vitro)]TJ /F4 1 Tf 3.1167 0 TD [(.)-439.2(Virology)]TJ -20.5361 -1.1223 TD [(283,)-336(197206.)]TJ -.8844 -1.1284 TD [(Ojkic,)-408(D.,)-410.5(and)-407.2(Nagy,)-402.9(E.)-410.8(\(2003\).)-402(Antibody)-410.2(response)-406.6(and)-407.2(virus)]TJ .8844 -1.1223 TD [(tissue)-343.7(distribution)-341.9(in)-341.3(chickens)-341.7(inoculated)-347.8(with)-342.6(wild-type)-337(and)]TJ 0 -1.1284 TD [(recombinant)-338.2(fowl)-333.3(adenoviruses.)-337.7(Vaccine)-342.1(22,)-329.7(4248.)]TJ -.8844 -1.1223 TD [(Olive,)-462.9(M.,)-450.9(Eisenlohr,)-459.1(L.,)-459.6(Flomenberg,)-453.3(N.,)]TJ /F7 1 Tf 18.1208 0 TD [(et)-455.3(al.)]TJ /F4 1 Tf 2.6715 0 TD [(\(2002\).)-456.9(The)]TJ -19.9079 -1.1284 TD [(adenovirus)-315.7(capsid)-312.8(protein)-311.4(hexon)-309.9(contains)-318.6(a)-309.3(highly)-310.8(conserved)]TJ 0 -1.1223 TD [(human)-437.5(CD4)]TJ /F9 1 Tf 5.2148 0 TD (+)Tj /F4 1 Tf 1.1528 0 TD [(T-cell)-439.3(epitope.)-435.3(Hum.)-434.7(Gene)-431.4(Ther.)-436(13,)-433.4(1167)]TJ -6.3676 -1.1284 TD (1178.)Tj -.8844 -1.1223 TD [(Ord,)-553.3(E.,)-551.1(Shirley,)-546.1(R.,)-554(McClure,)-552(J.,)]TJ /F7 1 Tf 15.2237 0 TD [(et)-552.8(al.)]TJ /F4 1 Tf 2.8605 0 TD [(\(2013\).)-548.4(Combined)]TJ -17.1998 -1.1284 TD [(antiapoptotic)-524(and)-510.9(antioxidant)-520.1(approach)-516.2(to)-518.1(acute)-519(neuropro-)]TJ 0 -1.1223 TD [(tection)-349.3(for)-346.6(stroke)-347.5(in)-341.3(hypertensive)-350.1(rats.)-347.3(J.)-340.9(Cereb.)-351.8(Blood)-340.4(Flow)]TJ 0 -1.1284 TD [(Metab.)-337.3(33,)-335.8(12151224.)]TJ -.8844 -1.1223 TD [(Ostapchuk,)-528.4(P.,)-521.6(and)-523.1(Hearing,)-525.2(P.)-521.5(\(2001\).)-517.9(Pseudopackaging)-526.7(of)]TJ .8844 -1.1284 TD [(adenovirus)-285.2(type)-278.7(5)-274.6(genomes)-282.6(into)-280(capsids)-281.5(containing)-276.5(the)-284.6(hexon)]TJ 0 -1.1223 TD [(proteins)-298.4(of)-301.5(adenovirus)-297.4(serotypes)-302.5(B,)-297.8(D,)-294.6(or)-301.5(E.)-294.9(J.)-298.2(Virol.)-296.3(75,)-299.2(45)]TJ 0 -1.1284 TD (51.)Tj -.8844 -1.1223 TD [(Pahl,)-269.4(J.H.,)-263.5(Verhoeven,)-268(D.H.,)-265.9(Kwappenberg,)-263.7(K.M.,)]TJ /F7 1 Tf 20.5239 0 TD [(et)-260.1(al.)]TJ /F4 1 Tf 2.2872 0 TD (\(2012\).)Tj -21.9268 -1.1284 TD [(Adenovirus)-343.6(type)-339.7(35,)-341.9(but)-335.3(not)-341.4(type)-339.7(5,)-341.8(stimulates)-340.8(NK)-338.9(cell)-343.3(acti-)]TJ 0 -1.1223 TD [(vation)-369.9(via)-363.9(plasmacytoid)-371.2(dendritic)-370.2(cells)-367(and)-364.5(TLR9)-369(signaling.)]TJ 0 -1.1284 TD [(Mol.)-334.7(Immunol.)-337.4(51,)-329.7(91100.)]TJ -.8844 -1.1223 TD [(Parker,)-260.9(A.L.,)-254(Fisher,)-252.9(K.D.,)-259.8(Oupicky,)-256.4(D.,)]TJ /F7 1 Tf 16.3277 0 TD [(et)-254(al.)]TJ /F4 1 Tf 2.2689 0 TD [(\(2005\).)-255.7(Enhanced)]TJ -17.7122 -1.1284 TD [(gene)-381(transfer)-374.9(activity)-379.3(of)-374.7(peptide-targeted)-379.5(gene-delivery)-376(vec-)]TJ 0 -1.1223 TD [(tors.)-337(J.)-334.8(Drug)-333.8(Target.)-336.3(13,)-329.7(3951.)]TJ -.8844 -1.1284 TD [(Parker,)-535.3(A.L.,)-534.6(Waddington,)-533.5(S.N.,)-535.6(Nicol,)-530(C.G.,)]TJ /F7 1 Tf 19.9872 0 TD [(et)-528.5(al.)]TJ /F4 1 Tf 2.8239 0 TD (\(2006\).)Tj -21.9268 -1.1223 TD [(Multiple)-545.2(vitamin)-545.9(K-dependent)-548.2(coagulation)-549.2(zymogens)-545(pro-)]TJ 0 -1.1284 TD [(mote)-693(adenovirus-mediated)-696.3(gene)-698.2(delivery)-687.8(to)-695(hepatocytes.)]TJ T* [(Blood)-334.3(108,)-336(25542561.)]TJ -.8844 -1.1223 TD [(Parker,)-388.9(A.L.,)-388.2(Waddington,)-387.1(S.N.,)-389.2(Buckley,)-391.9(S.M.,)]TJ /F7 1 Tf 20.2739 0 TD [(et)-388.2(al.)]TJ /F4 1 Tf 2.5373 0 TD (\(2009\).)Tj -21.9268 -1.1284 TD [(Effect)-417.8(of)-411.3(neutralizing)-410.8(sera)-413(on)-408.9(factor)-415.9(x-mediated)-411.3(adenovirus)]TJ 0 -1.1223 TD [(serotype)-339.8(5)-329.5(gene)-338.3(transfer.)-338.4(J.)-328.7(Virol.)-339(83,)-329.7(479483.)]TJ -.8844 -1.1284 TD [(Parks,)-357(R.,)-346.6(Evelegh,)-352.4(C.,)-352.7(and)-352.3(Graham,)-354.4(F.)-350.8(\(1999\).)-353.2(Use)-353(of)-350.3(helper-)]TJ .8844 -1.1223 TD [(dependent)-287.8(adenoviral)-289.7(vectors)-284.8(of)-283.2(alternative)-292.9(serotypes)-284.2(permits)]TJ 0 -1.1284 TD [(repeat)-338.5(vector)-334.3(administration.)-338(Gene)-333.8(Ther.)-338.4(6,)-335.7(15651573.)]TJ -.8844 -1.1223 TD [(Perreau,)-301.8(M.,)-298.4(and)-297.4(Kremer,)-301.8(E.J.)-300.3(\(2006\).)-298.4(The)-299.3(conundrum)-300.2(between)]TJ .8844 -1.1284 TD [(immunological)-238.9(memory)-238.3(to)-237.6(adenovirus)-236.4(and)-236.4(their)-237.9(use)-235.5(as)-235.4(vectors)]TJ 0 -1.1223 TD [(in)-335.2(clinical)-334.7(gene)-338.3(therapy.)-334.5(Mol.)-334.7(Biotechnol.)-336.3(34,)-335.8(247256.)]TJ -.8844 -1.1284 TD [(Perreau,)-551.9(M.,)-542.4(Welles,)-548.4(H.C.,)-549.7(Pellaton,)-541.5(C.,)]TJ /F7 1 Tf 17.8525 0 TD [(et)-546.7(al.)]TJ /F4 1 Tf 2.8483 0 TD [(\(2012\).)-548.4(The)]TJ -19.8164 -1.1223 TD [(number)-391.2(of)-386.9(Toll-like)-391.7(receptor)-389.9(9-agonist)-390.1(motifs)-391.1(in)-384(the)-388.3(adeno-)]TJ 0 -1.1284 TD [(virus)-617.6(genome)-618.8(correlates)-624.7(with)-617(induction)-619.8(of)-618.6(dendritic)-620.2(cell)]TJ 0 -1.1223 TD [(maturation)-437(by)-427.2(adenovirus)-431.6(immune)-430.6(complexes.)-433(J.)-432.4(Virol.)-430.5(86,)]TJ 0 -1.1284 TD (62796285.)Tj -.8844 -1.1223 TD [(Pichla-Gollon,)-618.7(S.L.,)-621.3(Drinker,)-614.8(M.,)-615.6(Zhou,)-618.6(X.,)]TJ /F7 1 Tf 19.8164 0 TD [(et)-619.9(al.)]TJ /F4 1 Tf 2.9947 0 TD (\(2007\).)Tj -21.9268 -1.1284 TD [(Structure-based)-386.7(identication)-380.5(of)-374.7(a)-382.5(major)-378.3(neutralizing)-380.3(site)-380.9(in)]TJ 0 -1.1223 TD [(an)-333.8(adenovirus)-340.1(hexon.)-334.4(J.)-334.8(Virol.)-332.9(81,)-329.7(16801689.)]TJ 26.1291 70.8975 TD [(Piersanti,)-421.1(S.,)-417.9(Astrologo,)-424.1(L.,)-416.9(Licursi,)-422.2(V.,)]TJ /F7 1 Tf 17.0047 0 TD [(et)-418.7(al.)]TJ /F4 1 Tf 2.5983 0 TD [(\(2013\).)-420.3(Differ-)]TJ -18.7186 -1.1223 TD [(entiated)-414.6(neuroprogenitor)-412.9(cells)-409.7(incubated)-415.3(with)-409.7(human)-413.2(or)-411.3(ca-)]TJ 0 -1.1284 TD [(nine)-1041.1(adenovirus,)-1041.6(or)-1045.6(lentiviral)-1040.1(vectors)-1047.2(have)-1039.8(distinct)]TJ 0 -1.1223 TD [(transcriptome)-339.4(proles.)-332.3(Plos)-331.4(One)-335.6(8,)-335.7(e69808.)]TJ -.8844 -1.1283 TD [(Pu)21.2(rk)21.8(ay)19.9(as)14.7(t)12.6(h)0(a)19.9(,)-317.2(A.)22.6(,)-317.2(D)0(i)23.1(t)0(t)19.2(y)0(,)-305.2(S)0(.)21.3(E)0(.)16.2(,)-311.1(Su)21.2(,)-317.2(J)12.9(.,)]TJ /F7 1 Tf 14.4003 0 TD [(et)-302.8(al)18.6(.)]TJ /F4 1 Tf 9.2951 0 0 9.2951 466.5825 683.3195 Tm [(\(2)15.7(00)24.1(5a)19.9(\).)-307.5(Ge)18.3(no)24.1(mi)19(c)-315.4(a)0(n)19.9(d)]TJ -15.8702 -1.1223 TD [(bi)18.6(oi)24.7(nf)15.7(or)21.8(ma)20.3(ti)19.2(cs)-662.3(an)19.9(al)20.5(ys)18.9(is)-657.5(of)-661.3(HA)21(dV)16.4(-4)21.8(,)-671(a)-669.2(hu)18(m)12.5(a)0(n)-657.1(a)0(d)19.9(e)0(n)13.8(o)0(v)24.1(i)0(r)16.3(u)0(s)]TJ 0 -1.1284 TD [(ca)21.8(us)18.9(in)18.6(g)-225.8(a)0(c)15.7(u)0(t)24.7(e)-230(re)17.6(s)12.9(p)0(i)18.6(r)0(a)17.6(t)12.6(or)15.7(y)-225.8(d)0(i)24.7(s)0(e)14.7(a)0(s)20.8(e)0(:)-217.4(i)0(m)19(p)0(l)18.6(i)12.6(ca)15.7(t)12.6(i)0(o)18.6(n)0(s)-219(f)0(o)21.8(r)-228.1(ge)19.9(ne)-218(t)12.6(h)0(e)19.9(r)0(a)17.6(p)0(y)]TJ 0 -1.1223 TD [(an)19.9(d)-323.4(v)0(a)19.9(c)0(c)15.7(i)12.6(ne)-315.6(ve)19.9(ct)20.5(or)-313.7(de)19.9(ve)13.8(l)12.6(o)0(p)18(m)12.5(en)19.9(t.)-316.8(J)12.9(.)-323.3(Vi)17(ro)21.8(l.)-316.8(79)18(,)-323.3(2)0(5)24.1(5)0(9)18()0(2)18(5)0(7)24.1(2)0(.)]TJ -.8844 -1.1284 TD [(Purkayastha,)-243.7(A.,)-245.8(Su,)-247.2(J.,)-243.4(Carlisle,)-245.9(S.,)]TJ /F7 1 Tf 14.443 0 TD [(et)-247.9(al.)]TJ /F4 1 Tf 2.2506 0 TD [(\(2005b\).)-243.6(Genomic)-247.9(and)]TJ -15.8092 -1.1223 TD [(bioinformatics)-401.8(analysis)-397(of)-399.1(HAdV-7,)-398.3(a)-394.7(human)-401(adenovirus)-401.1(of)]TJ 0 -1.1284 TD [(species)-291.9(B1)-291.7(that)-296.4(causes)-292.3(acute)-293.3(respiratory)-295.5(disease:)-297.5(implications)]TJ 0 -1.1223 TD [(for)-242.9(vector)-242.8(development)-250.5(in)-243.7(human)-242.4(gene)-246.9(therapy.)-243(Virology)-241.8(332,)]TJ 0 -1.1284 TD (114129.)Tj -.8844 -1.1284 TD [(Quinn,)-569(K.M.,)-562.5(Da)-573.3(Costa,)-563.4(A.,)-569.1(Yamamoto,)-570.9(A.,)]TJ /F7 1 Tf 19.914 0 TD [(et)-565.1(al.)]TJ /F4 1 Tf 2.891 0 TD (\(2013\).)Tj -21.9206 -1.1223 TD [(Comparative)-404(analysis)-403.1(of)-399.1(the)-400.5(magnitude,)-404.7(quality,)-400(phenotype,)]TJ 0 -1.1284 TD [(and)-504.8(protective)-508.7(capacity)-510.9(of)-508.8(simian)-508.8(immunodeciency)-507.8(virus)]TJ 0 -1.1223 TD [(gag-specic)-412.5(CD8)]TJ /F9 1 Tf 7.3008 0 TD (+)Tj /F4 1 Tf 1.1284 0 TD [(T)-404.6(cells)-409.6(following)-412.1(human-,)-409.6(simian-,)-407.7(and)]TJ -8.4291 -1.1284 TD [(chimpanzee-derived)-370.6(recombinant)-374.8(adenoviral)-369(vector)-364.8(immuni-)]TJ 0 -1.1223 TD [(zation.)-331.5(J.)-334.8(Immunol.)-337.4(190,)-329.9(27202735.)]TJ -.8844 -1.1284 TD [(Raman,)-306.3(S.,)-302(Hsu,)-306.2(T.H.,)-308.9(Ashley,)-310.2(S.L.,)-304.2(and)-303.5(Spindler,)-308.4(K.R.)-305.7(\(2009\).)]TJ .8844 -1.1223 TD [(Usage)-308.7(of)-313.7(integrin)-310.9(and)-309.6(heparan)-314.8(sulfate)-314.7(as)-308.6(receptors)-316(for)-310(mouse)]TJ 0 -1.1284 TD [(adenovirus)-334(type)-333.6(1.)-335.7(J.)-334.8(Virol.)-332.9(83,)-335.8(28312838.)]TJ -.8844 -1.1223 TD [(Raper,)-400.6(S.E.,)-401.7(Chirmule,)-401.3(N.,)-398.3(Lee,)-401.2(F.S.,)]TJ /F7 1 Tf 15.8336 0 TD [(et)-400.4(al.)]TJ /F4 1 Tf 2.5556 0 TD [(\(2003\).)-402(Fatal)-401.2(sys-)]TJ -17.5048 -1.1284 TD [(temic)-373.5(inammatory)-379.2(response)-376.1(syndrome)-372.3(in)-371.8(a)-376.4(ornithine)-372.1(trans-)]TJ 0 -1.1223 TD [(carbamylase)-724.5(decient)-716.9(patient)-721.3(following)-723.2(adenoviral)-716.7(gene)]TJ 0 -1.1284 TD [(transfer.)-332.3(Mol.)-334.6(Genet.)-339.6(Metab.)-337.3(80,)-329.7(148158.)]TJ -.8844 -1.1223 TD [(Rasmussen,)-548.2(U.B.,)-549.7(Benchaibi,)-548.3(M.,)-548.5(Meyer,)-547.5(V.,)]TJ /F7 1 Tf 19.9506 0 TD [(et)-546.7(al.)]TJ /F4 1 Tf 2.8544 0 TD (\(1999\).)Tj -21.9206 -1.1284 TD [(Novel)-378(human)-382.7(gene)-381(transfer)-387.1(vectors:)-381.9(evaluation)-384.4(of)-380.8(wild-type)]TJ 0 -1.1223 TD [(and)-242.5(recombinant)-246.7(animal)-245.6(adenoviruses)-246.1(in)-243.7(human-derived)-243.8(cells.)]TJ 0 -1.1284 TD [(Hum.)-331(Gene)-339.9(Ther.)-332.3(10,)-335.8(25872599.)]TJ -.8844 -1.1223 TD [(Reddy,)-583.1(P.S.,)-579.6(Idamakanti,)-588.2(N.,)-587.4(Babiuk,)-582.7(L.A.,)]TJ /F7 1 Tf 19.4322 0 TD [(et)-583.3(al.)]TJ /F4 1 Tf 2.9276 0 TD (\(1999a\).)Tj -21.4754 -1.1284 TD [(Porcine)-380(adenovirus-3)-385.4(as)-381.8(a)-382.5(helper-dependent)-386.7(expression)-388(vec-)]TJ 0 -1.1223 TD [(tor.)-331.6(J.)-334.8(Gen.)-335.6(Virol.)-332.9(80)-335.7(\(Pt)-334.4(11\),)-332.2(29092916.)]TJ -.8844 -1.1284 TD [(Reddy,)-412.3(P.S.,)-414.9(Idamakanti,)-423.5(N.,)-416.6(Hyun,)-410.9(B.H.,)]TJ /F7 1 Tf 17.7976 0 TD [(et)-418.7(al.)]TJ /F4 1 Tf 2.5922 0 TD [(\(1999b\).)-414.4(De-)]TJ -19.5054 -1.1223 TD [(velopment)-258.2(of)-258.8(porcine)-261.2(adenovirus-3)-263.4(as)-259.8(an)-260.7(expression)-259.9(vector.)-261.2(J.)]TJ 0 -1.1284 TD [(Gen.)-335.6(Virol.)-332.9(80)-335.7(\(Pt)-328.3(3\),)-338.1(563570.)]TJ -.8844 -1.1223 TD [(Roberts,)-267.1(D.M.,)-269.7(Nanda,)-273.1(A.,)-270.2(Havenga,)-271.5(M.J.,)]TJ /F7 1 Tf 17.2425 0 TD [(et)-266.2(al.)]TJ /F4 1 Tf 2.2933 0 TD [(\(2006\).)-267.9(Hexon-)]TJ -18.6515 -1.1284 TD [(chimaeric)-592.2(adenovirus)-596.3(serotype)-596(5)-591.8(vectors)-589.7(circumvent)-600.3(pre-)]TJ 0 -1.1223 TD [(existing)-332.1(anti-vector)-340.4(immunity.)-334.1(Nature)-335.9(441,)-329.9(239243.)]TJ -.8844 -1.1284 TD [(Robinson,)-449.8(M.,)-450.9(Li,)-453(B.,)-450.3(Ge,)-451.4(Y.,)]TJ /F7 1 Tf 13.1194 0 TD [(et)-449.2(al.)]TJ /F4 1 Tf 2.6593 0 TD [(\(2009\).)-450.8(Novel)-451.2(immuno-)]TJ -14.8943 -1.1223 TD [(competent)-372.2(murine)-372.4(tumor)-368(model)-376(for)-364.9(evaluation)-378.3(of)-368.6(condition-)]TJ 0 -1.1284 TD [(ally)-753.8(replication-competent)-761(\(oncolytic\))-757(murine)-756.6(adenoviral)]TJ 0 -1.1223 TD [(vectors.)-333.6(J.)-334.8(Virol.)-332.9(83,)-335.8(34503462.)]TJ -.8844 -1.1284 TD (Roge)Tj 1.7261 .0427 TD ()Tj .3843 -.0427 TD [(e,)-352.1(S.,)-350.8(Grellier,)-349.6(E.,)-349.8(Bernard,)-354.4(C.,)]TJ /F7 1 Tf 12.9792 0 TD [(et)-351.6(al.)]TJ /F4 1 Tf 2.458 0 TD [(\(2010\).)-347.1(Inuence)-354.5(of)]TJ -16.6631 -1.1223 TD [(chimeric)-368.3(human-bovine)-365.2(bers)-363(on)-366.2(adenoviral)-369(uptake)-362.5(by)-366.2(liver)]TJ 0 -1.1284 TD [(cells)-269.4(and)-266.9(the)-272.4(antiviral)-272(immune)-265.9(response.)-272.5(Gene)-272.8(Ther.)-271.3(17,)-262.6(880)]TJ T* (891.)Tj -.8844 -1.1223 TD [(R)13.4(o)0(g)18(o)0(z)19.9(h)0(i)18.6(n)0(,)-573.5(V)0(.)16.5(N)0(.)16.5(,)-585.6(Lo)22.2(gu)18(no)24.1(v,)-579.6(D.)22.6(Y.)16.5(,)-585.6(S)0(h)21.2(c)0(h)19.9(e)0(b)13.8(l)12.6(i)12.6(a)0(k)13.8(o)0(v)24.1(,)-585.6(D.)16.5(V.)22.6(,)]TJ /F7 1 Tf 23.4028 0 TD [(et)-577.2(al)18.6(.)]TJ /F4 1 Tf -22.5184 -1.1284 TD [(\(2)21.8(01)18(1\))21.8(.)-268.4(A)0(n)-258(e)0(f)17.6()0(c)23.1(i)0(e)14.4(n)0(t)-255.9(m)12.5(et)14.4(ho)24.1(d)-268.5(f)0(o)21.8(r)-270.8(t)12.6(h)0(e)-260.7(d)0(e)19.9(l)0(i)19.2(v)0(e)19.9(r)0(y)-258.8(o)0(f)-258.8(t)12.6(he)-260.7(i)12.6(n)0(t)18.6(e)0(r)17.6(l)12.6(eu)13.8(ki)24.7(n-)]TJ 0 -1.1223 TD [(2)-335.6(g)0(e)19.9(n)0(e)-321.7(t)0(o)-329.1(h)0(u)24.1(m)0(a)14.2(n)-329.5(he)13.8(m)12.5(a)0(t)20.5(o)0(p)18(o)0(i)18.6(e)0(t)20.5(i)12.6(c)-339.8(c)0(e)21.8(l)0(l)19.2(s)-334.7(us)18.9(in)18.6(g)-335.6(t)12.6(he)-327.8(b)21.2(er)17.6(-m)22.2(od)18(i)21.8(ed)]TJ 0 -1.1284 TD [(re)17.6(c)14(o)0(m)18.5(b)0(i)18.6(n)0(a)19.9(n)0(t)-316.9(a)14(de)13.8(no)24.1(vi)18.6(ru)21.8(s.)-316.5(Ac)18.3(t)12.6(a)-327.6(Na)18.3(t)12.6(.)-323.3(3,)-317.4(10)24.1(0)18(10)18(6.)]TJ -.8844 -1.1223 TD [(Romanczuk,)-457.5(H.,)-453.2(Galer,)-457.8(C.E.,)-452.4(Zabner,)-452.7(J.,)]TJ /F7 1 Tf 17.4682 0 TD [(et)-455.3(al.)]TJ /F4 1 Tf 2.6654 0 TD [(\(1999\).)-456.9(Mod-)]TJ -19.2492 -1.1284 TD [(ication)-456(of)-460(an)-455.8(adenoviral)-460.5(vector)-456.3(with)-458.5(biologically)-458.6(selected)]TJ 0 -1.1223 TD [(peptides:)-269.4(a)-266.6(novel)-266.6(strategy)-272.1(for)-267.3(gene)-271.3(delivery)-266.9(to)-268.1(cells)-269.4(of)-271(choice.)]TJ 0 -1.1284 TD [(Hum.)-331(Gene)-339.9(Ther.)-332.3(10,)-335.8(26152626.)]TJ -.8844 -1.1223 TD [(Rowe,)-389.4(W.P.,)-392(Huebner,)-397.7(R.J.,)-388.7(Gilmore,)-391.9(L.K.,)]TJ /F7 1 Tf 18.3526 0 TD [(et)-388.2(al.)]TJ /F4 1 Tf 2.5373 0 TD [(\(1953\).)-395.9(Is)22.7(o-)]TJ -20.0055 -1.1284 TD [(l)12.6(a)0(t)14.4(i)12.6(on)-305.2(of)-307.6(a)-315.4(c)14(yt)18.6(op)18(at)20.5(ho)18(ge)19.9(ni)18.6(c)-315.4(a)0(g)19.9(e)0(n)19.9(t)-316.7(fr)19.5(om)-304.8(hu)18(m)12.5(a)0(n)-309.5(a)14(de)19.9(no)18(id)18.6(s)-316.4(u)0(n)24.1(d)0(e)13.8(r)0(-)]TJ 0 -1.1223 TD [(go)24.1(in)18.6(g)-421(s)0(p)18.9(o)0(n)18(t)12.6(an)19.9(eo)19.9(us)-414.1(de)19.9(ge)19.9(ne)19.9(ra)17.6(t)12.6(i)0(o)18.6(n)-421(i)12.6(n)-421(t)12.6(i)0(s)19.5(s)0(u)18.9(e)-425.2(c)14(u)0(l)18.6(t)0(u)18.6(r)0(e)17.6(.)-420.9(P)15.3(r)0(o)15.7(c)0(.)-407(S)0(o)21.2(c)0(.)]TJ 0 -1.1284 TD [(Ex)22.2(p.)-232(Bi)19.9(ol)18.6(.)-237.9(M)0(e)14.5(d)0(.)-225.9(8)0(4)18(,)-237.9(57)18(0)18(57)24.1(3.)]TJ -.8844 -1.1223 TD [(Roy,)-322.5(S.,)-320.3(Shirley,)-326.5(P.S.,)-323.5(McClelland,)-327.5(A.,)-319(and)-321.8(Kaleko,)-327.5(M.)-322.7(\(1998\).)]TJ .8844 -1.1284 TD [(Circumvention)-521.5(of)-527.1(immunity)-523.1(to)-518.1(the)-522.5(adenovirus)-529.2(major)-518.6(coat)]TJ 0 -1.1223 TD [(protein)-335.7(hexon.)-334.4(J.)-328.7(Virol.)-339(72,)-329.7(68756879.)]TJ -.8844 -1.1284 TD [(Roy,)-328.6(S.,)-332.5(Gao,)-329.6(G.P.,)-328.2(Lu,)-331.6(Y.,)]TJ /F7 1 Tf 11.4666 0 TD [(et)-333.3(al.)]TJ /F4 1 Tf 2.4214 0 TD [(\(2004\).)-328.9(Characterization)-339.7(of)-332(a)]TJ -13.0036 -1.1223 TD [(family)-646.2(of)-649.1(chimpanzee)-649.7(adenoviruses)-654.8(and)-645.1(development)-653.1(of)]TJ /F3 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(CIRCUMVENTING)-339.9(ANTIVECTOR)-341.1(IMMUNITY)]TJ 53.0113 0 TD (297)Tj ET endstream endobj 40 0 obj <> endobj 41 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 42 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 70.2425 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(molecular)-313.5(clones)-312.8(for)-310(gene)-307.9(transfer)-313.9(vectors.)-315.3(Hum.)-306.6(Gene)-315.5(Ther.)]TJ 0 -1.1223 TD [(15,)-335.8(519530.)]TJ -.8844 -1.1284 TD [(Roy,)-523.7(S.,)-521.6(Clawson,)-522.5(D.S.,)-523.4(Calcedo,)-524.2(R.,)]TJ /F7 1 Tf 16.5777 0 TD [(et)-522.4(al.)]TJ /F4 1 Tf 2.7995 0 TD [(\(2005\).)-524(Use)-523.8(of)]TJ -18.4929 -1.1223 TD [(chimeric)-484.2(adenoviral)-478.8(vectors)-486(to)-475.4(assess)-481.5(capsid)-483.6(neutralization)]TJ 0 -1.1283 TD [(determinants.)-337(Virology)-333.3(333,)-336(207214.)]TJ -.8844 -1.1223 TD [(Roy,)-352.9(S.,)-356.9(Clawson,)-357.9(D.S.,)-358.7(Adam,)-353.7(V.S.,)]TJ /F7 1 Tf 15.5896 0 TD [(et)-351.6(al.)]TJ /F4 1 Tf 2.4702 0 TD [(\(2011a\).)-351.5(Construc-)]TJ -17.1754 -1.1284 TD [(tion)-286.1(of)-283.2(gene)-289.6(transfer)-289.5(vectors)-284.8(based)-288.8(on)-286.9(simian)-283.2(adenovirus)-291.3(7.)-280.8(J.)]TJ 0 -1.1223 TD [(Gen.)-335.7(Virol.)-332.9(92,)-335.8(17491753.)]TJ -.8844 -1.1284 TD [(Roy,)-615.2(S.,)-619.2(Medina-Jaszek,)-620(A.,)-617.9(Wilson,)-619.3(M.J.,)]TJ /F7 1 Tf 19.3163 0 TD [(et)-613.8(al.)]TJ /F4 1 Tf 2.9886 0 TD (\(2011b\).)Tj -21.4205 -1.1223 TD [(Creation)-363.2(of)-362.5(a)-364.2(panel)-368.4(of)-362.5(vectors)-364(based)-362(on)-360.1(ape)-368.7(adenovirus)-364.5(iso-)]TJ 0 -1.1284 TD [(lates.)-336.5(J.)-334.8(Gene)-333.8(Med.)-333.3(13,)-335.8(1725.)]TJ -.8844 -1.1223 TD [(Rux,)-383.4(J.J.,)-389.1(and)-382.8(Burnett,)-389.4(R.M.)-382.6(\(2000\).)-389.8(Type-specic)-390.2(epitope)-386.4(lo-)]TJ .8844 -1.1284 TD [(cations)-440.4(revealed)-440.6(by)-439.4(X-ray)-438.1(crystallographic)-441.5(study)-438.4(of)-435.7(adeno-)]TJ T* [(virus)-337(type)-333.6(5)-329.5(hexon.)-334.4(Mol.)-334.7(Ther.)-338.4(1,)-329.6(1830.)]TJ -.8844 -1.1223 TD [(Sakurai,)-404.5(F.)-399.6(\(2008\).)-402(Development)-404.6(of)-399.1(a)-400.8(replication-incompetent)]TJ .8844 -1.1284 TD [(adenovirus)-437.7(vector)-431.9(derived)-438.1(from)-431.7(subgroup)-435.6(B)-431.9(adenovirus)-431.6(se-)]TJ 0 -1.1223 TD [(rotype)-336.2(35.)-329.7(Yakuga.)-340.3(Zasshi)-334(128,)-336(17511761.)]TJ -.8844 -1.1284 TD [(Sakurai,)-300.8(F.,)-295.9(Mizuguchi,)-300.7(H.,)-300.7(and)-297.4(Hayakawa,)-301.8(T.)-301(\(2003\).)-298.4(Efcient)]TJ .8844 -1.1223 TD [(gene)-271.3(transfer)-271.2(into)-261.7(human)-272.9(CD34)]TJ /F9 1 Tf 12.8694 0 TD (+)Tj /F4 1 Tf .9881 0 TD [(cells)-269.4(by)-268.7(an)-266.8(adenovirus)-266.9(type)]TJ -13.8575 -1.1284 TD [(35)-335.7(vector.)-334.4(Gene)-333.8(Ther.)-338.4(10,)-329.7(10411048.)]TJ -.8844 -1.1223 TD [(Sakurai,)-404.5(F.,)-393.5(Nakamura,)-407.7(S.I.,)-396.1(Akitomo,)-403.6(K.,)]TJ /F7 1 Tf 17.8525 0 TD [(et)-400.4(al.)]TJ /F4 1 Tf 2.5556 0 TD [(\(2009\).)-402(Ade-)]TJ -19.5236 -1.1284 TD [(novirus)-410.5(serotype)-419.1(35)-408.9(vector-mediated)-416.1(transduction)-418.5(following)]TJ 0 -1.1223 TD [(direct)-626.5(administration)-630.7(into)-621.5(organs)-628.6(of)-624.7(nonhuman)-627.1(primates.)]TJ 0 -1.1284 TD [(Gene)-333.8(Ther.)-338.4(16,)-329.7(297302.)]TJ -.8844 -1.1223 TD [(Schoehn,)-555.2(G.,)-556.9(El)-550.5(Bakkouri,)-560.9(M.,)-554.6(Fabry,)-553.1(C.M.,)]TJ /F7 1 Tf 19.9384 0 TD [(et)-559(al.)]TJ /F4 1 Tf 2.8666 0 TD (\(2008\).)Tj -21.9206 -1.1284 TD [(Three-dimensional)-340(structure)-335.6(of)-332(canine)-336.2(adenovirus)-334(serotype)-339.8(2)]TJ 0 -1.1223 TD [(capsid.)-337.3(J.)-334.8(Virol.)-332.9(82,)-335.8(31923203.)]TJ -.8844 -1.1284 TD [(Schoggins,)-293.7(J.W.,)-296.7(Nociari,)-298.9(M.,)-292.3(Philpott,)-294.6(N.,)-294.6(and)-297.4(Falck-Pedersen,)]TJ .8844 -1.1223 TD [(E.)-630.3(\(2005\).)-633.8(Inuence)-628.9(of)-630.8(ber)-632.1(detargeting)-636.9(on)-628.5(adenovirus-)]TJ 0 -1.1284 TD [(mediated)-262.3(innate)-264.3(and)-260.8(adaptive)-262.7(immune)-259.8(activation.)-268(J.)-255.5(Virol.)-265.8(79,)]TJ 0 -1.1223 TD (1162711637.)Tj -.8844 -1.1284 TD [(Schumacher,)-273.2(L.,)-270.5(Ribas,)-270.6(A.,)-264.1(Dissette,)-276.1(V.B.,)]TJ /F7 1 Tf 17.2974 0 TD [(et)-266.2(al.)]TJ /F4 1 Tf 2.2933 0 TD [(\(2004\).)-267.9(Human)]TJ -18.7064 -1.1223 TD [(dendritic)-242.1(cell)-239.6(maturation)-241.8(by)-232.1(adenovirus)-242.5(transduction)-241.6(enhances)]TJ 0 -1.1284 TD [(tumor)-410.7(antigen-specic)-416.2(T-cell)-408.8(responses.)-412(J.)-414.1(Immunother.)-411.5(27,)]TJ 0 -1.1223 TD (191200.)Tj -.8844 -1.1284 TD [(Segura,)-368.3(M.M.,)-371.1(Puig,)-368.9(M.,)-365.5(Monfar,)-368.9(M.,)-371.6(and)-364.5(Chillo)]TJ 19.7737 .0427 TD ()Tj .4147 -.0427 TD [(n,)-366.2(M.)-365.4(\(2012\).)]TJ -19.3041 -1.1223 TD [(Chromatography)-519(purication)-519.7(of)-514.9(canine)-519.1(adenoviral)-521.5(vectors.)]TJ 0 -1.1284 TD [(Hum.)-337.1(Gene)-333.8(Ther.)-332.3(Methods)-338.5(23,)-329.7(182197.)]TJ -.8844 -1.1223 TD [(Seiradake,)-352.2(E.,)-349.8(Henaff,)-351(D.,)-343.4(Wodrich,)-353(H.,)]TJ /F7 1 Tf 16.6387 0 TD [(et)-345.5(al.)]TJ /F4 1 Tf 2.4519 0 TD [(\(2009\).)-347.1(The)-348.1(cell)]TJ -18.2062 -1.1284 TD [(adhesion)-368(molecule)-372.1()52.4(CAR)50.6()-368.4(and)-364.5(sialic)-372.6(acid)-368.3(on)-366.2(human)-370.5(eryth-)]TJ 0 -1.1223 TD [(rocytes)-510.4(inuence)-510.1(adenovirus)]TJ /F7 1 Tf 12.4851 0 TD [(in)-512(vivo)]TJ /F4 1 Tf 3.4766 0 TD [(biodistribution.)-506.5(PLoS)]TJ -15.9617 -1.1284 TD [(Pathog.)-336.8(5,)-329.6(e1000277.)]TJ -.8844 -1.1223 TD [(Seshidhar)-324.5(Reddy,)-320.9(P.,)-314.2(Ganesh,)-321.1(S.,)-320.3(Limbach,)-321.5(M.P.,)]TJ /F7 1 Tf 20.408 0 TD [(et)-321.1(al.)]TJ /F4 1 Tf 2.397 0 TD (\(2003\).)Tj -21.9206 -1.1284 TD [(Development)-453.4(of)-441.8(adenovirus)-449.9(serotype)-449.6(35)-445.5(as)-448.8(a)-449.6(gene)-448.1(transfer)]TJ 0 -1.1223 TD [(vector.)-334.4(Virology)-339.4(311,)-329.9(384393.)]TJ -.8844 -1.1284 TD [(Sharma,)-404.5(A.,)-410.5(Bangari,)-406.4(D.S.,)-401.4(Tandon,)-409.6(M.,)]TJ /F7 1 Tf 17.1023 0 TD [(et)-406.5(al.)]TJ /F4 1 Tf 2.5739 0 TD [(\(2009a\).)-406.4(Com-)]TJ -18.7917 -1.1284 TD [(parative)-496.8(analysis)-500.7(of)-490.5(vector)-499(biodistribution,)-494.3(persistence)-499.7(and)]TJ 0 -1.1223 TD [(gene)-503(expression)-497.8(following)-497.5(intravenous)-504.3(delivery)-498.7(of)-496.6(bovine,)]TJ 0 -1.1284 TD [(porcine)-493(and)-486.5(human)-492.4(adenoviral)-491(vectors)-492.1(in)-493.7(a)-486.2(mouse)-491.6(model.)]TJ 0 -1.1223 TD [(Virology)-333.3(386,)-336(4454.)]TJ -.8844 -1.1284 TD [(Sharma,)-453.3(A.,)-447.1(Li,)-446.9(X.,)-453.2(Bangari,)-449.1(D.S.,)-450.2(and)-449.9(Mittal,)-453.5(S.K.)-444(\(2009b\).)]TJ .8844 -1.1223 TD [(Adenovirus)-288.7(receptors)-297.7(and)-285.2(their)-292.8(implications)-292.6(in)-286.4(gene)-289.6(delivery.)]TJ 0 -1.1284 TD [(Virus)-332.5(Res.)-338(143,)-336(184194.)]TJ -.8844 -1.1223 TD [(Sharma,)-550.9(A.,)-544.7(Bangari,)-552.8(D.S.,)-541.7(Vemula,)-552.8(S.V.,)-547.8(and)-547.5(Mittal,)-544.9(S.K.)]TJ .8844 -1.1284 TD [(\(2011\).)-353.2(Persistence)-350.1(and)-352.3(the)-351.7(state)-348.7(of)-350.3(bovine)-352.2(and)-346.2(porcine)-352.7(ade-)]TJ 0 -1.1223 TD [(noviral)-396.7(vector)-389.2(genomes)-398.5(in)-390.1(human)-388.8(and)-395(nonhuman)-395.3(cell)-392.1(lines.)]TJ 0 -1.1284 TD [(Virus)-332.5(Res.)-338(161,)-336(181187.)]TJ -.8844 -1.1223 TD [(Shashkova,)-390(E.V.,)-388.2(Cherenova,)-393.2(L.V.,)-388.2(Kazansky,)-392.7(D.B.,)-391.1(and)-382.8(Dor-)]TJ .8844 -1.1284 TD [(onin,)-286.7(K.)-288.5(\(2005\).)-286.2(Avian)-286.5(adenovirus)-291.3(vector)-291.6(CELO-TK)-291.4(displays)]TJ 0 -1.1223 TD [(anticancer)-359.1(activity)-354.9(in)-353.5(human)-352.2(cancer)-355.5(cells)-354.8(and)-352.3(suppresses)-356.3(es-)]TJ 0 -1.1284 TD [(tablished)-403.6(murine)-402.8(melanoma)-402.7(tumors.)-397.8(Cancer)-404.8(Gene)-400.9(Ther.)-405.5(12,)]TJ 0 -1.1223 TD (617626.)Tj -.8844 -1.1284 TD [(Shayakhmetov,)-638.5(D.M.,)-641.8(Papayannopoulou,)-639.3(T.,)-636.5(Stamatoyanno-)]TJ .8844 -1.1223 TD [(poulos,)-280.1(G.,)-282.4(and)-279.1(Lieber,)-281.4(A.)-282.4(\(2000\).)-280.1(Efcient)-283.9(gene)-283.5(transfer)-277.3(into)]TJ 27.0074 70.8975 TD [(human)-413.2(CD34\()]TJ /F9 1 Tf 5.9224 0 TD (+)Tj /F4 1 Tf .6099 0 TD [(\))-411.1(cells)-409.6(by)-415(a)-406.9(retargeted)-418.2(adenovirus)-413.3(vector.)-413.7(J.)]TJ -6.5323 -1.1223 TD [(Virol.)-339(74,)-329.7(25672583.)]TJ -.8844 -1.1284 TD [(Shayakhmetov,)-425(D.M.,)-416.1(Gaggar,)-421.9(A.,)-422.7(Ni,)-416.1(S.,)]TJ /F7 1 Tf 17.7915 0 TD [(et)-424.8(al.)]TJ /F4 1 Tf 2.5983 0 TD [(\(2005\).)-420.3(Ade-)]TJ -19.5054 -1.1223 TD [(novirus)-306.8(binding)-298.7(to)-304.7(blood)-299(factors)-305.4(results)-303.5(in)-304.7(liver)-305(cell)-300.6(infection)]TJ 0 -1.1283 TD [(and)-340.1(hepatotoxicity.)-335.1(J.)-334.8(Virol.)-332.9(79,)-335.8(74787491.)]TJ -.8844 -1.1223 TD [(Sheppard,)-368.6(M.,)-371.6(Werner,)-366(W.,)-370.6(Tsatas,)-368.8(E.,)]TJ /F7 1 Tf 16.2545 0 TD [(et)-363.8(al.)]TJ /F4 1 Tf 2.4885 0 TD [(\(1998\).)-365.4(Fowl)-370.4(ad-)]TJ -17.8586 -1.1284 TD [(enovirus)-518.6(recombinant)-515.1(expressing)-516.1(VP2)-517.2(of)-514.9(infectious)-515.8(bursal)]TJ 0 -1.1223 TD [(disease)-615.1(virus)-611.5(induces)-617.9(protective)-612.4(immunity)-608.5(against)-617.3(bursal)]TJ 9.2951 0 0 9.2951 321.2787 641.4802 Tm [(disease.)-340.7(Arch.)-332(Virol.)-339(143,)-329.9(915930.)]TJ -.8844 -1.1223 TD [(Shimizu,)-555.5(T.,)-551.1(Ichihara,)-548.6(M.,)-548.5(Yoshioka,)-554.5(Y.,)]TJ /F7 1 Tf 18.2367 0 TD [(et)-546.7(al.)]TJ /F4 1 Tf 2.8544 0 TD [(\(2012\).)-554.5(In-)]TJ -20.2068 -1.1284 TD [(travenous)-370.4(administration)-368.4(of)-362.5(polyethylene)-366.4(glycol-coated)-367(\(PE-)]TJ 0 -1.1223 TD [(Gylated\))-396.6(proteins)-389.9(and)-388.9(PEGylated)-387(adenovirus)-395(elicits)-390.5(an)-388.7(anti-)]TJ 0 -1.1284 TD [(PEG)-513(immunoglobulin)-511.2(M)-505.6(response.)-510.3(Biol.)-510.5(Pharm.)-509.9(Bull.)-510.5(35,)]TJ T* (13361342.)Tj -.8844 -1.1223 TD .01 Tc [(Shiratsuchi,)-380.4(T.,)-380.4(R)-1(ai)10(,)-386.1(U)-3.9(.,)-380.4(Kraus)10(e)-5.8(,)-380.4(A)-3.9(.,)]TJ /F7 1 Tf 15.6384 0 TD .0114 Tc [(et)-378.5(al)11.4(.)]TJ /F4 1 Tf 2.5678 0 TD .0118 Tc [(\(2)5.6(01)5.6(0\).)-378.6(R).8(epl)11.8(a)-10.4(ci)11.8(n)-6.2(g)]TJ -17.3218 -1.1284 TD .011 Tc [(a)-5.5(d)4.8(enoviral)-592.4(vector)-589.2(HVR1)-586.9(wi)11(t)-6.4(h)-593(a)-585(m)-.9(alaria)-591.1(B)-591.6(cell)-586.3(e).6(pit)11(o)-7(pe)]TJ 0 -1.1223 TD .0112 Tc [(impro)5(v)-1.1(es)-366.2(im)11.2(m)-6.5(u)-1.1(n)5(ogen)5(i)-.6(city)-361(an)]TJ 12.2351 0 TD .0103 Tc [(d)-368(c)-.1(i)10.3(r)-10(cumvents)-367.1(preexi)10.3(s)-6.8(ting)-368(i)-1.5(m)10.3(-)]TJ -12.2351 -1.1284 TD .0119 Tc [(mun)5.7(ity)-421.3(t)11.9(o)-427(adeno)5.7(v)-.4(iru)5.7(s)-420.4(in)-421.3(mice.)-415.1(J.)-421.2(Clin)5.7(.)-421.2(I)3.3(nv)5.7(es)11.9(t)-5.2(.)-421.2(12)5.7(0,)-421.2(3)5.7(6)-.4(8)5.7(8)-.4()]TJ 0 -1.1223 TD .0123 Tc [(370)6.1(1.)]TJ -.8844 -1.1284 TD 0 Tc [(Sh)15.1(i)12.6(v)0(e)19.9(r)0(,)-417.3(J)12.9(.W)19.8(.,)-414.9(an)19.9(d)-421(E)0(m)16.6(i)12.6(ni)18.6(,)-420.9(E)0(.)16.2(A)0(.)-410.4(\()0(2)21.8(0)0(0)18(4)0(\))21.8(.)-427(R)13.4(e)0(c)15.7(e)0(n)19.9(t)-420.4(ad)13.8(va)19.9(nc)19.9(es)-412.3(in)-414.5(t)12.6(h)0(e)]TJ .8844 -1.1223 TD [(de)13.8(ve)19.9(l)12.6(o)0(p)18(m)12.5(en)13.8(t)-292.3(o)0(f)-283.2(H)0(I)20.2(V)0(-)20.2(1)-292.9(va)19.9(cc)15.7(i)12.6(n)0(e)19.9(s)-298.1(us)18.9(i)12.6(n)0(g)-280.8(r)0(e)17.6(p)0(l)18.6(i)0(c)20.5(a)0(t)14.4(i)12.6(on)18(-i)22.4(nc)19.9(om)18.4(pe)19.9(te)14.4(nt)]TJ 0 -1.1284 TD [(ad)13.8(e)14(n)0(o)18(v)0(i)18.6(r)0(u)21.8(s)-322.5(ve)13.8(c)13.9(t)0(o)18.6(r)0(s)16.6(.)-323.3(An)22.5(nu)18(.)-323.3(R)0(e)21.2(v)0(.)-317.4(M)12.8(ed)19.9(.)-323.3(5)0(5)18(,)-323.3(35)18(5)24.1(37)18(2.)]TJ -.8844 -1.1223 TD [(Shmarov,)-607.8(M.M.,)-609(Cherenova,)-606.6(L.V.,)-607.8(Shashkova,)-603.4(E.V.,)]TJ /F7 1 Tf 23.3601 0 TD [(et)-607.7(al.)]TJ /F4 1 Tf -22.4757 -1.1284 TD [(\(2002\).)-274(Eukaryotic)-275.2(vectors)-272.6(of)-271(Celo)-271.3(avian)-270.8(adenovirus)-273(genome,)]TJ 0 -1.1223 TD [(carrying)-385.7(GFP)-379.8(and)-382.8(human)-376.6(IL-2)-385.3(genes.)-380.4(Mol.)-377.3(Gen.)-384.4(Mikrobiol.)]TJ 0 -1.1284 TD [(Virusol.)-338.4(2,)-335.7(3035.)]TJ -.8844 -1.1223 TD [(Skog,)-271.9(J.,)-273.9(Edlund,)-270.6(K.,)-276.3(Bergenheim,)-276.4(A.T.,)-272.3(and)-273(Wadell,)-268.7(G.)-276.3(\(2007\).)]TJ .8844 -1.1284 TD [(Adenoviruses)-298.4(16)-286.9(and)-291.3(CV23)-293.6(efciently)-292(transduce)-289.2(human)-291.2(low-)]TJ 0 -1.1223 TD [(passage)-438.8(brain)-433.6(tumor)-435.1(and)-431.6(cancer)-434.8(stem)-435.9(cells.)-434.1(Mol.)-432.2(Ther.)-436(15,)]TJ 0 -1.1284 TD (21402145.)Tj -.8844 -1.1223 TD [(So)15.1(ud)24.1(ai)14.4(s)12.9(,)-298.9(C.)19.4(,)-298.9(B)13.4(ou)18(ti)19.2(n,)-286.9(S.)21.3(,)-298.9(H)0(o)16.4(n)0(g)24.1(,)-298.9(S.)21.3(S.)15.2(,)]TJ /F7 1 Tf 14.4735 0 TD [(et)-290.6(al)18.6(.)]TJ /F4 1 Tf 2.3299 0 TD [(\(2)21.8(00)18(0\))21.8(.)-298.9(C)0(a)21.2(n)0(i)18.6(n)0(e)-291.2(a)14(de)13.8(no)24.1(-)]TJ -15.919 -1.1284 TD [(vi)18.6(ru)15.7(s)-468.9(t)0(y)18.6(p)0(e)-461.9(2)-469.8(at)14.4(t)12.6(a)0(c)15.7(h)0(m)24.5(e)0(n)13.8(t)-469.2(an)19.9(d)-475.9(i)12.6(nt)18.6(er)17.6(na)19.9(l)12.6(i)0(z)20.5(a)0(t)14.4(i)12.6(on)18(:)-469.2(c)0(o)19.9(x)0(s)18.9(a)0(c)15.7(k)0(i)18.6(e)0(v)19.9(i)12.6(ru)15.7(s)12.9(-)]TJ 0 -1.1223 TD [(ad)13.8(e)14(n)0(o)18(v)0(i)18.6(r)0(u)21.8(s)-719(re)17.6(ce)15.7(pt)24.7(or)15.7(,)-719.8(a)14(lt)19.2(er)17.6(na)19.9(ti)19.2(ve)-712(re)17.6(c)14(e)0(p)13.8(t)12.6(or)21.8(s,)-712.9(an)19.9(d)-719.8(a)14(n)-719.9(R)0(G)17.8(D)0(-)]TJ 0 -1.1284 TD [(in)18.6(de)19.9(pe)13.8(nd)24.1(en)19.9(t)-243.5(p)0(a)19.9(t)12.6(hw)16.4(ay)19.9(.)-237.9(J)0(.)-231.1(V)0(i)17(r)0(o)21.8(l)0(.)-231.4(7)0(4)18(,)-237.9(10)18(63)18(9)24.1(10)18(64)18(9.)]TJ -.8844 -1.1223 TD [(Soudais,)-452(C.,)-450.3(Laplace-Builhe,)-451.3(C.,)-450.3(Kissa,)-449.5(K.,)-447.1(and)-449.9(Kremer,)-448.2(E.J.)]TJ .8844 -1.1284 TD [(\(2001\).)-420.3(Preferential)-423.2(transduction)-418.5(of)-423.5(neurons)-415.3(by)-421.1(canine)-415.5(ade-)]TJ 0 -1.1223 TD [(novirus)-251.9(vectors)-248.2(and)-242.5(their)-250.1(efcient)-249.6(retrograde)-246.1(transport)]TJ /F7 1 Tf 21.8902 0 TD [(in)-243.7(vivo)]TJ /F4 1 Tf 2.702 0 TD (.)Tj -24.5921 -1.1284 TD [(FASEB)-338(J.)-334.8(15,)-329.7(22832285.)]TJ -.8844 -1.1223 TD [(Stephen,)-463.2(S.L.,)-456.6(Montini,)-462.2(E.,)-453.5(Sivanandam,)-461.3(V.G.,)]TJ /F7 1 Tf 20.1336 0 TD [(et)-461.4(al.)]TJ /F4 1 Tf 2.6776 0 TD (\(2010\).)Tj -21.9267 -1.1284 TD [(Chromosomal)-346.1(integration)-339.4(of)-338.1(adenoviral)-338.5(vector)-340.4(DNA)]TJ /F7 1 Tf 21.7987 0 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 2.7934 0 TD (.)Tj -24.5921 -1.1223 TD [(J.)-334.8(Virol.)-339(84,)-329.7(99879994.)]TJ -.8844 -1.1284 TD [(Stevenson,)-346.7(M.,)-347.2(Boos,)-346.1(E.,)-343.7(Herbert,)-350.6(C.,)]TJ /F7 1 Tf 15.7116 0 TD [(et)-345.5(al.)]TJ /F4 1 Tf 2.4519 0 TD [(\(2006\).)-347.1(Chick)-344.6(em-)]TJ -17.2791 -1.1223 TD [(bryo)-234.7(lethal)-239.3(orphan)-233.1(virus)-239.5(can)-234.5(be)-230.2(polymer-coated)-241.5(and)-236.4(retargeted)]TJ 0 -1.1284 TD [(to)-335.2(infect)-339.8(mammalian)-334.8(cells.)-336.5(Gene)-333.8(Ther.)-338.4(13,)-329.7(356368.)]TJ -.8844 -1.1223 TD [(Stevenson,)-676.1(M.,)-664.4(Hale,)-674.9(A.B.,)-665.6(Hale,)-674.9(S.J.,)]TJ /F7 1 Tf 17.8769 0 TD [(et)-668.7(al.)]TJ /F4 1 Tf 3.0984 0 TD [(\(2007\).)-670.4(In-)]TJ -20.0909 -1.1284 TD [(corporation)-696.6(of)-685.7(a)-693.6(laminin-derived)-687.6(peptide)-691.4(\(SIKVAV\))-694.3(on)]TJ T* [(polymer-modied)-449.2(adenovirus)-449.9(permits)-444.2(tumor-specic)-452.6(target-)]TJ 0 -1.1223 TD [(ing)-335.3(via)-333.4(alpha6-integrins.)-339.7(Cancer)-337.8(Gene)-333.8(Ther.)-338.4(14,)-329.7(335345.)]TJ -.8844 -1.1284 TD [(Stone,)-495.3(D.,)-489.8(Ni,)-495.4(S.,)-491.1(Li,)-489.6(Z.Y.,)]TJ /F7 1 Tf 12.229 0 TD [(et)-491.9(al.)]TJ /F4 1 Tf 2.7447 0 TD [(\(2005\).)-493.5(Development)-496.1(and)]TJ -14.0892 -1.1223 TD [(assessment)-393.8(of)-386.9(human)-382.7(adenovirus)-388.9(type)-388.5(11)-384.5(as)-381.8(a)-388.6(gene)-387.1(transfer)]TJ 0 -1.1284 TD [(vector.)-340.5(J.)-334.8(Virol.)-332.9(79,)-329.7(50905104.)]TJ -.8844 -1.1223 TD [(Sullivan,)-531.2(N.J.,)-525.7(Geisbert,)-523.8(T.W.,)-525.2(Geisbert,)-529.9(J.B.,)]TJ /F7 1 Tf 19.9994 0 TD [(et)-528.5(al.)]TJ /F4 1 Tf 2.8117 0 TD (\(2003\).)Tj -21.9267 -1.1284 TD [(Accelerated)-395.5(vaccination)-388.8(for)-383.2(Ebola)-390.5(virus)-385.8(haemorrhagic)-388.2(fever)]TJ 0 -1.1223 TD [(in)-335.2(non-human)-336.8(primates.)-332.8(Nature)-342(424,)-329.9(681684.)]TJ -.8844 -1.1284 TD [(Sumida,)-549.9(S.M.,)-545.5(Truitt,)-546.3(D.M.,)-544.2(Lemckert,)-547.7(A.A.,)]TJ /F7 1 Tf 19.9567 0 TD [(et)-546.8(al.)]TJ /F4 1 Tf 2.8544 0 TD (\(2005\).)Tj -21.9267 -1.1223 TD [(Neutralizing)-601.5(antibodies)-592.8(to)-591.3(adenovirus)-596.3(serotype)-589.9(5)-591.8(vaccine)]TJ 0 -1.1284 TD [(vectors)-406.7(are)-407.6(directed)-405.3(primarily)-404.4(against)-403.9(the)-406.6(adenovirus)-407.2(hexon)]TJ 0 -1.1223 TD [(protein.)-335.8(J.)-334.8(Immunol.)-337.4(174,)-329.9(71797185.)]TJ -.8844 -1.1284 TD [(Ta)18(ma)14.2(ni)24.7(ni)18.6(,)-231.8(A)0(.)22.6(,)-231.8(Ni)23.1(co)13.8(l)12.6(i)0(s)19.5(,)-231.8(E.)22.3(,)-225.7(B)0(o)19.3(n)0(i)18.6(z)0(z)15.7(a)0(t)20.5(o)0(,)-219.8(A)0(.)16.5(,)]TJ /F7 1 Tf 16.1996 0 TD [(et)-217.4(al)18.6(.)]TJ /F4 1 Tf 2.1896 0 TD [(\(2)21.8(00)18(6\))21.8(.)-231.8(I)0(n)21.8(t)12.6(er)17.6(ac)15.7(t)12.6(i)0(o)18.6(n)]TJ -17.5048 -1.1223 TD [(of)-417.4(a)14(d)0(e)19.9(n)0(o)18(v)0(i)18.6(r)0(u)21.8(s)-426.2(t)12.6(y)0(p)18(e)-419.1(5)-421()0(b)15.1(e)14(r)-423.3(w)0(i)17(t)12.6(h)-421(t)0(h)18.6(e)-425.2(c)14(o)0(x)18(s)0(a)20.8(c)0(k)13.8(i)12.6(ev)19.9(ir)16.3(us)-408(an)19.9(d)-421(a)0(d)13.8(e)14(-)]TJ 0 -1.1284 TD [(no)18(vi)18.6(ru)21.8(s)-511.6(r)0(e)23.7(c)0(e)15.7(p)0(t)18.6(o)0(r)-496.6(a)0(c)21.8(t)0(i)19.2(v)0(a)13.8(t)12.6(es)-497.6(in)18.6(a)17(m)12.5(m)12.5(a)0(t)14.4(o)0(r)21.8(y)-506.4(re)17.6(s)12.9(p)0(o)18(n)0(s)18.9(e)-510.6(i)12.6(n)-506.4(hu)18(m)12.5(a)0(n)]TJ 0 -1.1223 TD [(re)17.6(sp)18.9(ir)16.3(a)14(t)0(o)18.6(r)0(y)-313.7(c)0(e)15.7(l)12.6(ls)19.5(.)-323.3(J)0(.)-316.5(V)0(i)17(r)0(o)21.8(l)12.6(.)-323.3(8)0(0)18(,)-323.3(11)18(24)24.1(1)18(11)18(25)18(4.)]TJ -.8844 -1.1284 TD [(Tan,)-616.5(P.K.,)-608.8(Michou,)-613.8(A.I.,)-608.2(Bergelson,)-613.2(J.M.,)-608.8(and)-614.6(Cotten,)-612.6(M.)]TJ .8844 -1.1223 TD [(\(2001\).)-469.1(Dening)-472.7(CAR)-469(as)-467.2(a)-467.9(cellular)-471.8(receptor)-469.2(for)-468.6(the)-467.6(avian)]TJ /F3 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (298)Tj 43.6471 0 TD [(LOPEZ-GORDO)-336.9(ET)-338.7(AL.)]TJ ET endstream endobj 43 0 obj <> endobj 44 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>> endobj 45 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 67.9748 725.1588 Tm 0 0 0 1 k 0 Tc 0 Tw [(adenovirus)-413.3(CELO)-413.3(using)-407.9(a)-406.9(genetic)-408.9(analysis)-415.3(of)-405.2(the)-412.7(two)-410.1(viral)]TJ 0 -1.1223 TD [(bre)-339.4(proteins.)-335.1(J.)-328.7(Gen.)-335.7(Virol.)-339(82,)-329.7(14651472.)]TJ -.8844 -1.1284 TD [(Tandon,)-238.8(M.,)-237.4(Sharma,)-239.8(A.,)-239.7(Vemula,)-235.6(S.V.,)]TJ /F7 1 Tf 16.102 0 TD [(et)-235.7(al.)]TJ /F4 1 Tf 2.2323 0 TD [(\(2012\).)-237.4(Sequential)]TJ -17.4499 -1.1223 TD [(administration)-466(of)-460(bovine)-461.9(and)-462.1(human)-461.9(adenovirus)-462.1(vectors)-467.7(to)]TJ 0 -1.1283 TD [(overcome)-436.5(vector)-431.9(immunity)-437.7(in)-432.8(an)-431.4(immunocompetent)-432.6(mouse)]TJ 0 -1.1223 TD [(model)-339.4(of)-332(breast)-333.4(cancer.)-337.3(Virus)-338.6(Res.)-331.9(163,)-336(202211.)]TJ -.8844 -1.1284 TD [(Tang,)-287.3(J.,)-280(Olive,)-286(M.,)-286.2(Pulmanausahakul,)-287.9(R.,)]TJ /F7 1 Tf 17.2547 0 TD [(et)-284.5(al.)]TJ /F4 1 Tf 2.3238 0 TD [(\(2006\).)-286.2(Human)]TJ -18.6942 -1.1223 TD (CD8)Tj /F9 1 Tf 2.0554 0 TD (+)Tj /F4 1 Tf 1.0857 0 TD [(cytotoxic)-374(T)-374.1(cell)-373.8(responses)-369.2(to)-371.8(adenovirus)-376.7(capsid)-373.8(pro-)]TJ -3.1411 -1.1284 TD [(teins.)-338.4(Virology)-333.3(350,)-336(312322.)]TJ -.8844 -1.1223 TD [(Tang,)-378.8(R.,)-377.1(Li,)-373.7(K.,)-380(Wilson,)-375.3(M.,)]TJ /F7 1 Tf 12.6315 0 TD [(et)-376(al.)]TJ /F4 1 Tf 2.5129 0 TD [(\(2012\).)-371.5(Potent)-378.9(antietumor)]TJ -14.26 -1.1284 TD [(immunity)-553.6(in)-554.7(mice)-556.9(induced)-551.7(by)-555.3(vaccination)-559.5(with)-549.9(an)-553.4(ovine)]TJ 0 -1.1223 TD [(atadenovirus)-337.9(vector.)-334.4(J.)-334.8(Immunother.)-338.3(35,)-329.7(3241.)]TJ -.8844 -1.1284 TD [(Tarassishin,)-315.5(L.,)-307.1(Szawlowski,)-312.8(P.,)-308.1(Kidd,)-306.6(A.H.,)-314.7(and)-303.5(Russell,)-312.1(W.C.)]TJ .8844 -1.1284 TD [(\(2000\).)-304.5(An)-306.8(epitope)-307.1(on)-305.2(the)-302.9(adenovirus)-303.5(bre)-308.9(tail)-301.9(is)-309.9(common)-303.1(to)]TJ 0 -1.1223 TD [(all)-338.9(human)-333.9(subgroups.)-331.3(Arch.)-338.1(Virol.)-332.9(145,)-336(805811.)]TJ -.8844 -1.1284 TD [(Tian,)-384.3(X.,)-380(Su,)-375.3(X.,)-380(Li,)-379.8(H.,)]TJ /F7 1 Tf 10.4724 0 TD [(et)-376(al.)]TJ /F4 1 Tf 2.5129 0 TD [(\(2011\).)-383.7(Construction)-376.4(and)-382.8(char-)]TJ -12.1009 -1.1223 TD [(acterization)-504.6(of)-502.7(human)-498.5(adenovirus)-504.8(serotype)-504.5(3)-494.2(packaged)-505.9(by)]TJ 0 -1.1284 TD [(serotype)-339.8(7)-329.5(hexon.)-334.4(Virus)-338.6(Res.)-331.9(160,)-336(214220.)]TJ -.8844 -1.1223 TD [(Tomko,)-502.4(R.P.,)-502.2(Xu,)-496(R.,)-505.2(and)-498.7(Philipson,)-501.8(L.)-496.1(\(1997\).)-499.6(HCAR)-501.2(and)]TJ .8844 -1.1284 TD [(MCAR:)-254.5(the)-254.1(human)-254.6(and)-254.7(mouse)-253.7(cellular)-252.2(receptors)-261.1(for)-249(subgroup)]TJ 0 -1.1223 TD [(C)-486.8(adenoviruses)-490.1(and)-486.5(group)-484.9(B)-480.7(coxsackieviruses.)-491.6(Proc.)-485.8(Natl.)]TJ 0 -1.1284 TD [(Acad.)-340(Sci.)-330.3(USA)-335.8(94,)-335.8(33523356.)]TJ -.8844 -1.1223 TD [(Tr)13.8(i)12.6(p)0(a)19.9(t)0(h)18.6(y)0(,)-408.9(S)0(.)21.3(K)0(.)16.5(,)-420.9(B)13.4(l)0(a)14.4(c)0(k)19.9(,)-420.9(H.)22.6(B.)19.4(,)-420.9(G)0(o)16.4(l)12.6(dw)16.4(as)20.8(se)20.8(r,)-411.2(E.)16.2(,)-420.9(a)14(nd)-415(Le)18(i)12.6(d)0(e)19.9(n)0(,)-408.9(J)0(.)19(M)0(.)]TJ .8844 -1.1284 TD [(\(1)15.7(99)24.1(6\))15.7(.)-286.7(I)0(m)22.2(m)0(u)18.4(n)0(e)-279(r)0(e)17.6(s)12.9(po)18(ns)18.9(es)-278.1(to)-280.3(t)12.6(r)0(a)17.6(n)0(s)18.9(g)0(e)19.9(n)0(e)19.9(-)0(e)17.6(n)0(c)19.9(o)0(d)18(e)0(d)-279(p)0(r)21.8(o)0(t)18.6(e)0(i)20.5(n)0(s)-280(l)12.6(im)19(it)]TJ 0 -1.1223 TD [(th)18.6(e)-376.4(s)0(t)19.5(a)0(b)19.9(i)0(l)19.2(i)0(t)19.2(y)-372.2(of)-368.6(ge)19.9(ne)-364.3(ex)19.9(pr)15.7(e)14(s)0(s)13.7(i)12.6(on)-366.2(af)17.6(t)12.6(e)0(r)-366.7(i)12.6(nj)18.6(ec)15.7(t)12.6(i)0(o)18.6(n)-372.2(of)-368.6(re)17.6(pl)18.6(i)12.6(c)0(a)15.7(t)12.6(io)18.6(n-)]TJ 0 -1.1284 TD [(de)13.8(fe)23.7(ct)14.4(i)12.6(v)0(e)-315.6(a)0(d)19.9(e)0(n)19.9(o)0(v)18(i)12.6(ru)15.7(s)-322.5(v)0(e)19.9(c)0(t)20.5(o)0(r)15.7(s)12.9(.)-323.3(N)0(a)18.3(t)0(.)-316.8(M)12.8(ed)19.9(.)-323.3(2)0(,)-317.4(5)0(4)24.1(5)0()18(5)0(5)18(0)0(.)]TJ -.8844 -1.1223 TD [(Tuboly,)-471.9(T.,)-465.7(Nagy,)-470(E.,)-471.8(and)-468.2(Derbyshire,)-472.1(J.B.)-467.9(\(1993\).)-469.1(Potential)]TJ .8844 -1.1284 TD [(viral)-548.9(vectors)-553.1(for)-547.9(the)-546.9(stimulation)-550.5(of)-551.5(mucosal)-550.4(antibody)-547.1(re-)]TJ 0 -1.1223 TD [(sponses)-368.5(against)-367.2(enteric)-368.6(viral)-372.1(antigens)-367.4(in)-365.7(pigs.)-365.1(Res.)-368.5(Vet.)-365.6(Sci.)]TJ 0 -1.1284 TD [(54,)-335.8(345350.)]TJ -.8844 -1.1223 TD [(Tutykhina,)-372.3(I.L.,)-364.6(Shmarov,)-363.8(M.M.,)-365(Logunov,)-368.9(D.I.,)]TJ /F7 1 Tf 20.3166 0 TD [(et)-369.9(al.)]TJ /F4 1 Tf 2.4946 0 TD (\(2008\).)Tj -21.9268 -1.1284 TD [(Construction)-345.9(of)-338.1(the)-339.5(vector)-346.5(based)-337.6(on)-341.8(the)-339.5(CELO)-346.2(avian)-337.9(adeno-)]TJ 0 -1.1223 TD [(virus)-361.4(genome)-362.6(providing)-356.2(enhanced)-359.5(expression)-363.6(of)-356.4(secreted)-366.5(al-)]TJ 0 -1.1284 TD [(kaline)-343.6(phosphatase)-347.3(gene)-338.3(in)-341.3(a)-345.9(non-permissive)-341.1(system)]TJ /F7 1 Tf 21.8231 0 TD [(in)-341.3(vitro)]TJ /F4 1 Tf -21.8231 -1.1223 TD (and)Tj /F7 1 Tf 1.781 0 TD [(in)-335.2(vivo)]TJ /F4 1 Tf 2.7934 0 TD [(.)-335.5(Mol.)-334.7(Gen.)-329.6(Mikrobiol.)-336.7(Virusol.)-338.4(4,)-329.6(2630.)]TJ -5.4588 -1.1284 TD [(Ulasov,)-450.5(I.V.,)-443.6(Rivera,)-448.9(A.A.,)-448.9(Han,)-445.4(Y.,)]TJ /F7 1 Tf 15.8092 0 TD [(et)-443.1(al.)]TJ /F4 1 Tf 2.6471 0 TD [(\(2007\).)-444.7(Targeting)]TJ -17.5719 -1.1223 TD [(adenovirus)-602.4(to)-603.5(CD80)-598.6(and)-602.4(CD86)-598.6(receptors)-602.6(increases)-603.6(gene)]TJ 0 -1.1284 TD [(transfer)-435.9(efciency)-437.5(to)-432.8(malignant)-434.5(glioma)-436.5(cells.)-434.1(J.)-432.4(Neurosurg.)]TJ 0 -1.1223 TD [(107,)-336(617627.)]TJ -.8844 -1.1284 TD [(Varnavski,)-305(A.N.,)-302.5(Schlienger,)-304.9(K.,)-300.7(Bergelson,)-302.1(J.M.,)]TJ /F7 1 Tf 20.4507 0 TD [(et)-296.7(al.)]TJ /F4 1 Tf 2.3604 0 TD (\(2003\).)Tj -21.9268 -1.1223 TD [(Efcient)-399.8(transduction)-406.3(of)-393(human)-401(monocyte-derived)-400.4(dendritic)]TJ 0 -1.1284 TD [(cells)-421.8(by)-408.9(chimpanzee-derived)-425.5(adenoviral)-417.8(vector.)-413.7(Hum.)-416.4(Gene)]TJ 0 -1.1223 TD [(Ther.)-338.4(14,)-329.7(533544.)]TJ -.8844 -1.1284 TD [(Vellinga,)-332.8(J.,)-322.7(Van)-323.4(der)-330.2(Heijdt,)-322.2(S.,)-326.4(and)-327.9(Hoeben,)-328.1(R.C.)-321.1(\(2005\).)-328.8(The)]TJ .8844 -1.1223 TD [(adenovirus)-340.1(capsid:)-330.7(major)-335.6(progress)-337.6(in)-335.2(minor)-331.4(proteins.)-335.1(J.)-334.8(Gen.)]TJ 0 -1.1284 TD [(Virol.)-339(86,)-329.7(15811588.)]TJ -.8844 -1.1284 TD [(Voeks,)-457(D.,)-453.2(Martiniello-Wilks,)-453.5(R.,)-450.3(Madden,)-453.9(V.,)]TJ /F7 1 Tf 20.1458 0 TD [(et)-455.3(al.)]TJ /F4 1 Tf 2.6654 0 TD (\(2002\).)Tj -21.9268 -1.1223 TD [(Gene)-388.7(therapy)-383.2(for)-377.1(prostate)-388(cancer)-386(delivered)-381.1(by)-384.5(ovine)-376.4(adeno-)]TJ 0 -1.1284 TD [(virus)-379.7(and)-370.6(mediated)-378.2(by)-378.4(purine)-372.8(nucleoside)-378(phosphorylase)-376.2(and)]TJ 0 -1.1223 TD [(udarabine)-342(in)-329.1(mouse)-339.1(models.)-332.6(Gene)-333.8(Ther.)-338.4(9,)-329.6(759768.)]TJ -.8844 -1.1284 TD [(Vogels,)-438.3(R.,)-432(Zuijdgeest,)-430.1(D.,)-434.9(van)-431.6(Rijnsoever,)-435.9(R.,)]TJ /F7 1 Tf 20.1885 0 TD [(et)-430.9(al.)]TJ /F4 1 Tf 2.6227 0 TD (\(2003\).)Tj -21.9268 -1.1223 TD [(Replication-decient)-425.1(human)-419.3(adenovirus)-419.4(type)-412.9(35)-421.1(vectors)-418.9(for)]TJ 0 -1.1284 TD [(gene)-356.6(transfer)-356.6(and)-352.3(vaccination:)-357.8(efcient)-353.3(human)-352.2(cell)-355.5(infection)]TJ 0 -1.1223 TD [(and)-327.9(bypass)-320.5(of)-325.9(preexisting)-326.9(adenovirus)-321.8(immunity.)-321.9(J.)-322.6(Virol.)-326.8(77,)]TJ 0 -1.1284 TD (82638271.)Tj -.8844 -1.1223 TD [(Volk,)-312.7(A.L.,)-308.9(Rivera,)-308.7(A.A.,)-314.7(Kanerva,)-310.4(A.,)]TJ /F7 1 Tf 16.163 0 TD [(et)-315(al.)]TJ /F4 1 Tf 2.3787 0 TD [(\(2003\).)-310.5(Enhanced)]TJ -17.6573 -1.1284 TD [(adenovirus)-254.7(infection)-248.2(of)-246.6(melanoma)-250.2(cells)-251.1(by)-250.4(ber-modication:)]TJ 0 -1.1223 TD [(incorporation)-415.8(of)-411.3(RGD)-410.9(peptide)-410.8(or)-411.3(Ad5/3)-410.4(chimerism.)-417.9(Cancer)]TJ 0 -1.1284 TD [(Biol.)-339.7(Ther.)-332.3(2,)-335.7(511515.)]TJ -.8844 -1.1223 TD [(Vrati,)-355.4(S.,)-350.8(Macavoy,)-354.5(E.S.,)-352.9(Xu,)-349.6(Z.Z.,)]TJ /F7 1 Tf 14.815 0 TD [(et)-357.7(al.)]TJ /F4 1 Tf 2.4641 0 TD [(\(1996\).)-353.2(Construction)]TJ -16.3947 -1.1284 TD [(and)-364.5(transfection)-364(of)-362.5(ovine)-364.2(adenovirus)-364.5(genomic)-362.2(clones)-367.7(to)-359.6(res-)]TJ 0 -1.1223 TD [(cue)-338.2(modied)-336.5(viruses.)-334.6(Virology)-333.3(220,)-336(200203.)]TJ -.8844 -1.1284 TD [(Vujanovic,)-528.7(L.,)-526.7(Whiteside,)-530(T.L.,)-528.8(Potter,)-527.7(D.M.,)]TJ /F7 1 Tf 19.9994 0 TD [(et)-522.3(al.)]TJ /F4 1 Tf 2.8117 0 TD (\(2009\).)Tj -21.9268 -1.1223 TD [(Regulation)-671.6(of)-661.3(antigen)-667(presentation)-666.7(machinery)-667.9(in)-664.5(human)]TJ 27.0135 70.8975 TD [(dendritic)-333.6(cells)-330.4(by)-335.7(recombinant)-332.1(adenovirus.)-334.1(Cancer)-331.7(Immunol.)]TJ 0 -1.1223 TD [(Immunother.)-332.2(58,)-335.8(121133.)]TJ -.8844 -1.1284 TD [(Walsh,)-386.1(M.P.,)-386.9(Seto,)-391.4(J.,)-389.8(Liu,)-386.1(E.B.,)]TJ /F7 1 Tf 13.9124 0 TD [(et)-388.2(al.)]TJ /F4 1 Tf 2.5373 0 TD [(\(2011\).)-389.8(Computational)]TJ -15.5652 -1.1223 TD [(analysis)-342.1(of)-344.2(two)-349.1(species)-346.7(C)-340.4(human)-346.1(adenoviruses)-349.8(provides)-341.7(evi-)]TJ 0 -1.1283 TD [(dence)-336.6(of)-332(a)-333.7(novel)-333.7(virus.)-337.1(J.)-328.7(Clin.)-339.7(Microbiol.)-334.8(49,)-329.7(34823490.)]TJ -.8844 -1.1223 TD [(Wang,)-381.3(I.J.,)-380.1(Jhuang,)-382.4(M.C.,)-382.7(Chen,)-387.8(Y.H.,)]TJ /F7 1 Tf 9.2951 0 0 9.2951 462.7274 672.888 Tm [(et)-382.1(al.)]TJ /F4 1 Tf 2.519 0 TD [(\(2010\).)-383.7(Chitosan)]TJ -17.9744 -1.1284 TD [(modication)-364.5(of)-356.4(adenovirus)-364.5(to)-359.6(modify)-362(transfection)-364(efciency)]TJ 0 -1.1223 TD [(in)-335.2(bovine)-333.9(corneal)-332.5(epithelial)-340.6(cells.)-336.5(PLoS)-331.5(One)-335.6(5,)-335.7(e12085.)]TJ -.8844 -1.1284 TD [(Wang,)-436.2(C.H.,)-439.9(Chan,)-436.6(L.W.,)-433.7(Johnson,)-438.5(R.N.,)]TJ /F7 1 Tf 17.7244 0 TD [(et)-437(al.)]TJ /F4 1 Tf 2.6349 0 TD [(\(2011a\).)-436.9(The)]TJ -19.4749 -1.1223 TD [(transduction)-278.2(of)-283.2(Coxsackie)-279.5(and)-279.1(Adenovirus)-282.6(Receptor-negative)]TJ 0 -1.1284 TD [(cells)-787.8(and)-785.3(protection)-785.1(against)-788.1(neutralizing)-782.9(antibodies)-788(by)]TJ 0 -1.1223 TD [(HPMA-co-oligolysine)-743.8(copolymer-coated)-746.1(adenovirus.)-736.6(Bio-)]TJ 0 -1.1284 TD [(materials)-336.5(32,)-335.8(95369545.)]TJ -.8844 -1.1284 TD [(Wang,)-417.9(D.Y.,)-412.3(Liu,)-416.6(S.H.,)-419.7(Li,)-416.4(X.,)]TJ /F7 1 Tf 13.3573 0 TD [(et)-412.6(al.)]TJ /F4 1 Tf 2.5861 0 TD [(\(2011b\).)-420.5(Study)-411.7(on)-415(con-)]TJ -15.059 -1.1223 TD [(struction)-621.2(of)-624.7(chimeric)-624.4(adenovirus)-620.7(vector)-620.9(Ad5/11)-624(carrying)]TJ 0 -1.1284 TD [(human)-376.6(eGFP)-372(and)-376.7(endostatin-K5)-377.6(and)-376.7(its)-376.5(experimental)-378.6(inves-)]TJ 0 -1.1223 TD (tigation)Tj /F7 1 Tf 3.3912 0 TD [(in)-316.9(vitro)]TJ /F4 1 Tf 2.9886 0 TD [(.)-317.2(X)0(i)-318.5(Bao)-320.5(Yu)-319(Fen)-318.6(Zi)-318.8(Mian)-314.5(Yi)-318.4(Xue)-317.3(Za)-323.5(Zhi)-312.8(27,)]TJ -6.3798 -1.1284 TD (143145.)Tj -.8844 -1.1223 TD [(Wohlfart,)-428(C.)-425.8(\(1988\).)-420.3(Neutralization)-434.6(of)-423.5(adenoviruses:)-428.7(kinetics,)]TJ .8844 -1.1284 TD [(stoichiometry,)-338.4(and)-334(mechanisms.)-334.2(J.)-334.8(Virol.)-332.9(62,)-335.8(23212328.)]TJ -.8844 -1.1223 TD [(Wu,)-230.4(Q.,)-233.6(and)-236.4(Tikoo,)-233.9(S.K.)-236.7(\(2004\).)-231.3(Altered)-237.8(tropism)-232.6(of)-234.4(recombinant)]TJ .8844 -1.1284 TD [(bovine)-510.7(adenovirus)-510.9(type-3)-507(expressing)-510(chimeric)-514.7(ber.)-510.2(Virus)]TJ 0 -1.1223 TD [(Res.)-331.9(99,)-335.8(915.)]TJ -.8844 -1.1284 TD [(Wu,)-340.2(H.,)-337.3(Dmitriev,)-342.6(I.,)-338.1(Kashentseva,)-341(E.,)]TJ /F7 1 Tf 16.0837 0 TD [(et)-339.4(al.)]TJ /F4 1 Tf 2.4336 0 TD [(\(2002\).)-341.1(Construc-)]TJ -17.6329 -1.1223 TD [(tion)-353.2(and)-358.4(characterization)-363.5(of)-356.4(adenovirus)-352.3(serotype)-358.1(5)-360(packaged)]TJ 0 -1.1284 TD [(by)-329.6(serotype)-339.8(3)-329.5(hexon.)-334.4(J.)-334.8(Virol.)-332.9(76,)-335.8(1277512782.)]TJ -.8844 -1.1223 TD [(Xiang,)-378.1(Z.,)-386.4(Gao,)-378.3(G.,)-380(Reyes-Sandoval,)-387.3(A.,)]TJ /F7 1 Tf 17.2059 0 TD [(et)-382.1(al.)]TJ /F4 1 Tf 2.519 0 TD [(\(2002\).)-383.7(Novel,)]TJ -18.8405 -1.1284 TD [(chimpanzee)-326.4(serotype)-321.5(68-based)-322.1(adenoviral)-326.3(vaccine)-322.2(carrier)-325(for)]TJ 0 -1.1223 TD [(induction)-381.9(of)-386.9(antibodies)-385.4(to)-384(a)-388.6(transgene)-386.8(product.)-385.2(J.)-383.6(Virol.)-381.7(76,)]TJ 0 -1.1284 TD (26672675.)Tj -.8844 -1.1223 TD [(Xiang,)-396.4(Z.,)-398.6(Li,)-404.2(Y.,)-398.3(Cun,)-395.6(A.,)]TJ /F7 1 Tf 11.7044 0 TD [(et)-394.3(al.)]TJ /F4 1 Tf 2.5556 0 TD [(\(2006\).)-395.9(Chimpanzee)-406.3(adeno-)]TJ -13.3756 -1.1284 TD [(virus)-385.8(antibodies)-391.5(in)-390.1(humans,)-388.1(sub-Saharan)-392.9(Africa.)-393.2(Emerg.)-386.9(In-)]TJ 0 -1.1223 TD [(fect.)-334.1(Dis.)-336.1(12,)-329.7(15961599.)]TJ -.8844 -1.1284 TD [(Xu,)-343.5(Z.Z.,)-351.9(and)-346.2(Both,)-346.4(G.W.)-347.9(\(1998\).)-347.1(Altered)-347.6(tropism)-348.5(of)-350.3(an)-346(ovine)]TJ .8844 -1.1223 TD [(adenovirus)-352.3(carrying)-361.3(the)-351.7(ber)-357.7(protein)-354(cell)-355.5(binding)-353.6(domain)-357.8(of)]TJ 0 -1.1284 TD [(human)-333.9(adenovirus)-334(type)-333.6(5.)-335.7(Virology)-333.3(248,)-336(156163.)]TJ -.8844 -1.1223 TD [(Xu,)-563.1(Z.Z.,)-565.4(Hyatt,)-560.5(A.,)-569.1(Boyle,)-564.2(D.B.,)-561.9(and)-565.8(Both,)-566(G.W.)-561.4(\(1997\).)]TJ .8844 -1.1284 TD [(Construction)-400.8(of)-399.1(ovine)-400.8(adenovirus)-401.1(recombinants)-398.5(by)-396.7(gene)-405.4(in-)]TJ 0 -1.1223 TD [(sertion)-603.2(or)-606.4(deletion)-611.7(of)-600.3(related)-612.5(terminal)-607.5(region)-604.5(sequences.)]TJ 0 -1.1284 TD [(Virology)-333.3(230,)-336(6271.)]TJ -.8844 -1.1223 TD [(Xu,)-355.7(Z.Z.,)-358(Nevels,)-363.2(M.,)-353.3(MacAvoy,)-358(E.S.,)]TJ /F7 1 Tf 16.1691 0 TD [(et)-357.7(al.)]TJ /F4 1 Tf 2.4763 0 TD [(\(2000\).)-353.2(An)-361.7(ovine)]TJ -17.761 -1.1284 TD [(adenovirus)-346.2(vector)-346.5(lacks)-349.2(transforming)-345.9(ability)-344.5(in)-347.4(cells)-348.7(that)-345.2(are)]TJ 0 -1.1223 TD [(transformed)-374.9(by)-372.3(AD5)-369.5(E1A/B)-374.3(sequences.)-376.3(Virology)-376(270,)-366.5(162)]TJ 0 -1.1284 TD (172.)Tj -.8844 -1.1223 TD 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[(Y)-19.3(a)-1(m)-6.8(a)-19.3(gu)-19.3(ch)-19.3(i,)-251.1(T)-19.3(.)3(,)-251.1(K)-19.3(aw)-19.3(ab)-19.3(at)-19.3(a)-4.9(,)-245(K)-19.3(.)-2.8(,)-251.1(K)-19.3(oi)-19.3(zu)-19.3(mi)-19.3(,)-238.5(N)-19.3(.,)]TJ /F7 1 Tf 17.5292 0 TD 0 Tc [(e)14(t)-231.3(al)18.6(.)]TJ /F4 1 Tf 2.1896 0 TD [(\(2)21.8(00)18(7\))21.8(.)-231.8(R)13.4(ol)18.6(e)-230(o)0(f)]TJ -18.8344 -1.1284 TD [(M)12.8(y)0(D)16.4(8)0(8)-323.5(a)0(n)13.8(d)-335.6(TL)20.3(R9)-328.3(i)12.6(n)-341.7(t)12.6(h)0(e)-327.8(i)0(n)18.6(n)0(a)19.9(t)12.6(e)-339.8(i)0(m)19(m)12.5(un)18(e)-339.8(r)0(e)17.6(s)12.9(po)18(ns)18.9(e)-333.7(e)0(l)14.4(i)12.6(ci)20.5(te)14.4(d)-335.6(b)0(y)]TJ 0 -1.1223 TD -.0184 Tc [(s)-5.5(e)-18.4(ro)-18.4(ty)-18.4(pe)-327.7(5)-323.5(a)-18.4(de)-18.4(no)-18.4(vi)-18.4(ral)-329(v)-18.4(ec)-18.4(to)-18.4(rs)-5.5(.)-329.5(H)-18.4(um)-5.9(.)-329.5(G)-18.4(en)-18.4(e)-315.7(T)-18.4(he)-18.4(r.)-329.5(1)-18.4(8)5.7(,)-329.5(7)-18.4(53)-18.4()5.7(7)-18.4(62)-18.4(.)]TJ -.8844 -1.1284 TD 0 Tc [(Ya)18.3(o,)-311.3(X.)16.5(,)-317.2(Y)0(o)16.4(s)0(h)18.9(i)12.6(ok)18(a,)-315.5(Y.)22.6(,)-323.3(M)0(o)18.8(r)0(i)22.4(s)0(h)18.9(i)0(g)18.6(e)0(,)-315.5(T)0(.)22.3(,)]TJ /F7 1 Tf 15.5896 0 TD [(et)-315(al)18.6(.)]TJ /F4 1 Tf 2.3787 0 TD [(\(2)21.8(01)18(0\))21.8(.)-323.3(A)0(d)22.5(e)0(n)13.8(o)0(v)24.1(i)0(r)16.3(u)0(s)]TJ -17.084 -1.1223 TD [(ve)19.9(ct)20.5(or)-484.4(co)19.9(va)19.9(le)14.4(nt)18.6(l)12.6(y)-494.2(co)19.9(nj)18.6(ug)18(a)14(t)0(e)14.4(d)-494.2(t)12.6(o)-494.2(po)18(l)12.6(y)0(e)19.9(t)0(h)18.6(y)0(l)18.6(e)0(n)19.9(e)-492.3(gl)18.6(yc)19.9(ol)-487.7(wi)23.1(th)-487.6(a)]TJ 0 -1.1284 TD [(ca)21.8(nc)13.8(e)14(r)0(-)19.5(s)0(p)18.9(e)0(c)15.7(i)12.6(c)-288(pr)21.8(om)18.4(ot)18.6(e)14(r)-295.2(su)18.9(pp)18(re)23.7(ss)13.7(e)14(s)-298.1(t)12.6(h)0(e)-285.1(t)12.6(um)18.4(or)-283.2(gr)21.8(ow)16.4(t)12.6(h)-292.9(th)18.6(ro)15.7(ug)24.1(h)]TJ 0 -1.1223 TD [(s)12.9(y)0(s)18.9(t)0(e)20.5(m)0(i)19(c)-327.6(ad)19.9(m)12.5(i)0(n)18.6(i)0(s)19.5(t)0(r)16.3(a)0(t)20.5(i)0(o)18.6(n)0(.)-311.3(B)0(i)19.9(o)0(l)18.6(.)-323.3(Ph)21.2(ar)17.6(m.)-316.9(B)13.4(u)0(l)18.6(l)0(.)-316.8(3)0(3)24.1(,)-323.3(10)18(73)18(1)24.1(07)18(6.)]TJ -.8844 -1.1284 TD [(Ying,)-343.2(B.,)-346.6(Smith,)-343.7(K.,)-343.4(and)-346.2(Spindler,)-345(K.R.)-348.4(\(1998\).)-347.1(Mouse)-344.9(adeno-)]TJ .8844 -1.1223 TD [(virus)-471.2(type)-467.8(1)-469.8(early)-474.4(region)-470.4(1A)-465.4(is)-474.6(dispensable)-468.7(for)-474.7(growth)-467.7(in)]TJ 0 -1.1284 TD [(cultured)-334(broblasts.)-337.4(J.)-334.8(Virol.)-332.9(72,)-335.8(63256331.)]TJ -.8844 -1.1223 TD [(Youil,)-294(R.,)-297.8(Toner,)-295.9(T.J.,)-300.4(Su,)-296(Q.,)]TJ /F7 1 Tf 12.3875 0 TD [(et)-296.7(al.)]TJ /F4 1 Tf 2.3543 0 TD [(\(2002\).)-298.4(Hexon)-293.2(gene)-301.8(switch)]TJ -13.8575 -1.1284 TD 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