Major histocompatibility complex (MHC) class I molecules present peptides to T-cell antigen receptors on CD8 T-cells, leading to the activation of the lymphocytes. To evade recognition by HIV antigen-specific CDS+ cytotoxic T-lymphocytes (CTL), HIV decreases the expression of MHC class I molecules. The loss of these molecules on the cell surface may make HIV-infected cells less susceptible to destruction by natural killer (NK cells). We have recently demonstrated, however, that HIV-infected primary T-cells are not killed by NK cells despite a drastic reduction of surface expression of MHC class I molecules. One possible mechanism of escape from NK cell-mediated destruction may involve the expression of HLA-G on the surface of HIV-infected cells. We showed that activated CD4+ T-cells not expressing HLA-G begin to do so after infection with HIV. HLA-G is important in down-modulating immune responses mediated not only by NK cells, but also by CTL. The inhibitory effects of HLA-G are due to the interaction of HLA-G on the surface of target cells containing specific inhibitory receptors found on both NK cells and antigen-specific CDS+ T-cells. We propose that the novel finding of the expression of HLA-G on the surface of HIV-infected T-cells is responsible for the complete lack of killing of HIV-infected cells by NK cells. We will determine if HLA-G specifically is involved in the inhibition of NK cell-mediated cytotoxic responses targeted at infected cells. Moreover, we will determine if HIV antigen-specific CTL is prevented from killing infected cells through HLA-G. Finally, we will determine if HLA-G prevents production of beta-chemokines by CD8+T-cells and NK cells. If HLA-G is found to modulate NK cell- and CD8+ T cell-mediated responses, it would be advantageous to design therapies and vaccine approaches that include blocking HLA-G molecules on infected cells to prevent them from interacting with inhibitory molecules on lymphocytes.
| Planelles, Vicente; Barker, Edward (2010) Roles of Vpr and Vpx in modulating the virus-host cell relationship. Mol Aspects Med 31:398-406 |
| Ward, Jeffrey; Davis, Zachary; DeHart, Jason et al. (2009) HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog 5:e1000613 |
