HSV-2 Specifically Down Regulates HLA-C Expression to Render HSV-2-Infected DCs Susceptible to NK Cell Killing

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Abstract
Both NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are inhibited by MHC class I molecules. The inhibitory NK receptors recognize mainly MHC class I proteins and in this regard practically all of the HLA-C proteins are recognized by inhibitory NK cell receptors, while only certain HLA-A and HLA-B proteins interact with these receptors. Sophisticated viruses developed mechanisms to avoid the attack of both NK cells and CTLs through, for example, down regulation of HLA-A and HLA-B molecules to avoid CTL recognition, leaving HLA-C proteins on the cell surface to inhibit NK cell response. Here we provide the first example of a virus that through specific down regulation of HLA-C, harness the NK cells for its own benefit. We initially demonstrated that none of the tested HSV-2 derived microRNAs affect NK cell activity. Then we show that surprisingly upon HSV-2 infection, HLA-C proteins are specifically down regulated, rendering the infected cells susceptible to NK cell attack. We identified a motif in the tail of HLA-C that is responsible for the HSV-2-meduiated HLA-C down regulation and we show that the HLA-C down regulation is mediated by the viral protein ICP47. Finally we show that HLA-C proteins are down regulated from the surface of HSV-2 infected dendritic cells (DCs) and that this leads to the killing of DC by NK cells. Thus, we propose that HSV-2 had developed this unique and surprising NK cell-mediated killing strategy of infected DC to prevent the activation of the adaptive immunity. Approximately 20% of all humans are latently and asymptomatically infected with HSV-2. This suggests that the virus developed mechanisms to avoid immune cell detection; many of which are still unknown. Infected cells are killed mainly by two lymphocyte populations; NK cells and CTLs that belong to the innate and the adaptive immunity, respectively. While the killing machinery of these two cell types is similar, almost identical, the ways by which they discriminate between infected and uninfected cells is different. CTLs are activated, primarily by DCs, to become effector cells. They then recognize virus-derived peptides in the groove of MHC class I molecules and eliminate the virally infected cells. In contrast, NK cells recognize infected cells through several NK cell activating receptors, while the recognition of MHC class I proteins by NK cells leads to inhibition of NK cell killing. Viruses, such as HIV, developed mechanisms to interfere with the function of both NK cells and CTLs via targeting of specific MHC class I proteins. Here we show that HSV-2 developed a MHC class I-dependent mechanism in which the virus, through specific targeting of HLA-C by the viral protein ICP47, harness the NK cells for its own benefit, probably to avoid the activation of adaptive immune response.

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