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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI056923-01
Application #
6696533
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Plaeger, Susan F
Project Start
2003-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$228,000
Indirect Cost
Name
Upstate Medical University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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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