Natural killer (NK) cells are innate lymphocytes that are crucial in the immune surveillance against viruses. However, NK cells fail to control HIV-1. NK cells do not effectively lyse HIV-infected cells despite the ability of HIV-1 Nef to down modulate the ligands for NK cell inhibitory receptors, HLA-A and -B. Moreover, HIV-1 Vpr induces ligands, ULBP-1 and -2, to the activation receptor, NKG2D. The actions of Nef and Vpr are sufficient to activate NK cells but insufficient to trigger NK cells to release their cytolytic granules. For NK cells to degranulate they require the engagement of two receptors, NKG2D and NTB-A. Under normal conditions, NTB-A on NK cells is triggered by NTB-A on CD4+ T-cells. However, HIV-1 Vpu is able to down modulate NTB-A from the infected cells surface and in doing so prevents the responding NK cells from degranulating. Thus, Vpu protects the infected cell from lysis by NK cells. In order to understand Vpu's modulation of NTB-A and its consequence on the NK cell cytolytic response we will: 1) determine the mechanism by which Vpu, through NTB-A down modulation, suppresses NK cytolytic response, 2) determine how Vpu down modulates NTB-A and 3) determine whether and how Vpu from various subtypes and groups of HIV-1 and SIV strains are able to down modulate NTB-A. In the first aim, we will test the hypothesis that Vpu down modulation of NTB-A on HIV-infected target cells prevents the ability of specific intracellular signals originating from NTB-A on NK cells from inducing down stream signaling events involved in facilitating the release of lytic granules.
In Aim 1 we will alo examine whether the activation ligands to NK cell activation receptor, KIR3DS1 is able to trigger degranulation in the context of NTB-A down modulation. In the second aim, we will test the hypothesis that Vpu's cytoplasmic tail interferes with host cell proteins that are involved in transporting NTB-A from the trans-Golgi network to the plasma membrane. In the second Aim we will also determine whether and how the transmembrane (TM) portion of Vpu interacts with the TM portion of NTB-A. In the last aim, we will test the hypothesis that Vpu from specific HIV-1 subtypes and groups will have different efficiencies in modulating NTB-A. Moreover, we will determine whether Vpu's down modulation of NTB-A is limited to HIV-1 or whether SIV Vpu down modulates simian and human NTB-A as well. Knowledge of these mechanisms will undoubtedly lead to novel therapeutic interventions aimed at restoring the effectiveness of the NK compartment during HIV- 1 infection.

Public Health Relevance

This project will determine how HIV evades immune cells called natural killer cells. Natural killer cells are part of the first line of defense against HIV infection. The results from this study will provide insights on the mechanisms by which HIV avoids detection and destruction by the early immune response. These insights will point the way towards treatment strategies that will enhance the immune system's ability to control HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI065361-06A1
Application #
8263260
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2005-04-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$146,197
Indirect Cost
$40,558
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
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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 262:20-6
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
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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
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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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