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Viral downregulation of CD155 reveals strong effect of DNAM-1 in virus control by NK cells and macrophages

Cytomegaloviruses (CMVs) are species-specific herpesviruses causing severe disease in immunocompromised and immunologically immature hosts. The hallmark of all CMVs is the presence of a large range of so-called immune evasion genes targeting the host immune response. Therefore, viral mutants lacking these genes represent a perfect tool for understanding the physiological role of various immune response mechanisms. The poliovirus receptor (PVR or CD155), is a glycoprotein that is constitutively expressed under physiological conditions. It serves as a ligand for the adhesion molecule DNAM-1 (CD226), an activating receptor expressed on the majority of immune cells. PVR is also a ligand for TIGIT, an inhibitory receptor that inhibits NK and T cell cytotoxicity and for CD96 (Tactile), receptor with both activating and inhibitory functions. It has been reported that viral infections and tumorigenesis upregulate PVR expression, indicating a role of PVR as a stress induced molecule. However, it has been also shown that both HIV and HCMV encode proteins that reduce PVR surface expression of infected cells suggesting that the impact of PVR regulation on virus control is still poorly characterized. In addition, seeing that PVR binds both activating and inhibitory immune cell receptors, the ultimate consequence of this ligation is hardly predictable. In the present study we have shown that MCMV retains PVR inside of infected cells and we have characterized the viral gene involved. The deletion of the MCMV inhibitor of PVR dramatically enhanced the virus susceptibility to innate immune control in DNAM-1 dependent manner. Although the virus lacking the PVR inhibitor was more susceptible to NK cells, it appears that virus control was predominantly mediated by macrophages which displayed a dramatic increase of DNAM-1 expression and almost no inhibitory PVR receptors. Mice infected with virus lacking the PVR inhibitor had an elevated level of proinflammatory cytokines in their sera and a marked polarization of their macrophages towards inflammation with increased iNOS production. These results underscore the physiological role of DNAM-1 in virus control by NK cells and macrophages, indicating that the DNAM-1/PVR axis could play a more general role in immune response and virus control.

CD155; DNAM-1; cytomegaloviruses (CMVs); macrophages

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