HIV-1 avoids destruction by HIV-antigen specific cytotoxic T-lymphocytes (CTL) by decreasing the cell surface expression of human leukocyte antigen (HLA)-A and HLA-B, which are needed to trigger CTL. Natural killer (NK) cells, however, can destroy cells lacking MHC class I molecules since these molecules inhibit NK cell killing. Despite this fact, NK cells are unable to kill HIV-infected cells. Our long-term objective is to determine how HIV prevents NK cells from destroying the infected cells, even though the conditions for the NK cell cytotoxic response appear optimal. One explanation for the inability of NK cells to kill HIV- infected cell is the presence of HLA-C and HLA-E on the infected cell surface. However, HLA-C and HLA-E only prevent a subset of NK cells from killing HIV-infected cells. Another explanation for the lack of NK cell killing is that HIV-1 induces the expression of HLA-G on activated CD4+ T-cells. HLA-G inhibits NK cell cytotoxic responses. The central hypothesis of this proposal is that HIV prevents NK from killing infected cells and controlling viral replication by inducing the expression of HLA-G. To evaluate our objective, we will determine the role of HLA-G cell surface expression, in the context of HIV infection, in disabling NK cell function, and to dissect the required signaling events. This will be accomplished by directing small interfering (si)RNA to HLA-G in HIV-infected cells, and determining the ability of NK cells to become activated and kill HIV-infected cells with decreased HLA-G surface expression. We will also determine the mechanisms by which HIV infection of CD4+ cells induces surface expression of HLA-G. Finally, we will determine the effect of soluble HLA-G secreted by HIV-infected cells on NK cell cytotoxic responses. The overall significance of this study is to provide insight into the mechanism important for allowing HIV to counter cellular immune responses that are differentially regulated by MHC class I molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065361-05
Application #
7544526
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$317,200
Indirect Cost
Name
Rush University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Das, Bibhuti B; Opella, Stanley J (2016) Simultaneous cross polarization to (13)C and (15)N with (1)H detection at 60kHz MAS solid-state NMR. J Magn Reson 262:20-26
Davis, Zachary B; Cogswell, Andrew; Scott, Hamish et al. (2016) A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells. PLoS Pathog 12:e1005421
Boudreau, Jeanette E; Mulrooney, Tiernan J; Le Luduec, Jean-BenoƮt et al. (2016) KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV. J Immunol 196:3398-410
Zhang, Hua; Lin, Eugene C; Das, Bibhuti B et al. (2015) Structural determination of virus protein U from HIV-1 by NMR in membrane environments. Biochim Biophys Acta 1848:3007-3018
Ramirez, Peter W; Famiglietti, Marylinda; Sowrirajan, Bharatwaj et al. (2014) Downmodulation of CCR7 by HIV-1 Vpu results in impaired migration and chemotactic signaling within CD4? T cells. Cell Rep 7:2019-30
Park, Sang Ho; Yang, Chen; Opella, Stanley J et al. (2013) Resolution and measurement of heteronuclear dipolar couplings of a noncrystalline protein immobilized in a biological supramolecular assembly by proton-detected MAS solid-state NMR spectroscopy. J Magn Reson 237:164-8
Sauter, Daniel; Unterweger, Daniel; Vogl, Michael et al. (2012) Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. PLoS Pathog 8:e1003093
Manion, Maura; Rodriguez, Benigno; Medvik, Kathleen et al. (2012) Interferon-alpha administration enhances CD8+ T cell activation in HIV infection. PLoS One 7:e30306
Davis, Zachary B; Ward, Jeffrey P; Barker, Edward (2011) Preparation and use of HIV-1 infected primary CD4+ T-cells as target cells in natural killer cell cytotoxic assays. J Vis Exp :
Sowrirajan, Bharatwaj; Barker, Edward (2011) The natural killer cell cytotoxic function is modulated by HIV-1 accessory proteins. Viruses 3:1091-111

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