engleski

Differential Role OF α vβ 3 and α vβ 5 Integrins in Iinternalization and Transduction Efficacies of Wild Type and RGD4C Fiber-modified Adenoviruses

The RGD4C peptide has been used extensively for genetic retargeting of adenovirus type 5 (Ad5). In this study we used a model composed of a human laryngeal carcinoma cell line (HEp2) that expresses alpha v beta 5 and alpha v beta 1 but not alpha v beta 3 integrins, and HEp2 derived stably transfected cell lines with graded expression levels of the beta 3 subunit. In two of the transfected cell lines, low level expression of the beta 3 subunit led to expression of alpha v beta 3 without affecting the expression of other alpha v integrins. In the third cell line, high level expression of the beta 3 subunit led to greater expression of alpha v beta 3 integrin, but diminished expression of other alpha v integrins, namely, beta 5 and beta 1, as a result of competition for the alpha v subunit. We show here that alpha v beta 3 mediates the internalization of both wild type Ad5wt and fiber-modified Ad5RGD4C more successfully than other alpha v integrins, since the amount of internalized virus increased in parallel with increasing levels of alpha v beta 3 integrin in the three stable transfectants. Transduction efficacy was increased for both viruses in the two cell lines with moderate levels of alpha v beta 3 expression. However, in the cell line where alpha v beta 3 integrin had replaced other alpha v integrins, the transduction efficacy dramatically decreased. This discrepancy between internalization and transduction efficacy is likely due to the crucial role of alpha v beta 5 in membrane permeabilization. Finally, we found a similar difference in transduction efficacy between Ad5wt and Ad5RGD4C in each cell line, regardless of the ratio of alpha v beta 3 and beta 5 integrins. Therefore, we suppose that neither alpha v integrin is responsible for the superior transduction efficacy of Ad5RGD4C observed in this cell model.

adenovirus; transduction; internalization; integrins

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