Natural killer (NK) cells are cytotoxic effector cells of the innate immune system that have been shown to play a central role in the control of viral infections, and increasing evidence suggests that NK cells also contribute to the control of HIV-1 infection. The presence of particular NK cell receptors, killer immunoglobuline-like receptors (KIRs) encoded in conjunction with their HLA class I ligands is associated with slower HIV-1 disease progression and better control of viremia, and NK cells expressing these protective KIRs have been shown to strongly inhibit HIV-1 replication in vitro. The goals of this proposal are to determine whether NK cells can mediate antiviral activity in HIV-1-infected individuals in vivo, and to identify the precise receptor/ligand interactions involved in the NK cell recognition of infected cells. The PI proposes to test the hypothesis that NK cells can impose significant immune pressure on HIV-1 in vivo, forcing the virus to evade NK cell mediated immune pressure by selecting for NK cell escape variants. If successful, these studies will establish NK cells as a new important effector cell population that, in concert with virus-specific CD8+ T cells and B cells, contributes to the control of HIV-1 replication in infected individuals and to HIV-1 diversity. These findings will have an important impact on the HIV-1 field by providing the rational to harness this arm of the antiviral immune response for HIV-1 vaccine design, in particular given the recent description in mice that NK cells can mediate immunological memory to viral infections.

Public Health Relevance

Increasing evidence suggests that NK cells contribute to the control of HIV-1 infection. The goals of this proposal are to determine whether NK cells can mediate antiviral activity in HIV-1-infected individuals in vivo, and to identify the precise receptor/ligand interactions involved in the NK cell recognition of infected cells. The results from these studies will have an important impact on the HIV-1 field by providing the rational to harness this arm of the antiviral immune response for HIV-1 vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067031-07
Application #
8286152
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2005-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$709,199
Indirect Cost
$302,199
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Garcia-Beltran, Wilfredo F; Hölzemer, Angelique; Martrus, Gloria et al. (2016) Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 17:1067-74
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Jost, Stephanie; Moreno-Nieves, Uriel Y; Garcia-Beltran, Wilfredo F et al. (2013) Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection. Retrovirology 10:74
Fadda, Lena; Körner, Christian; Kumar, Swati et al. (2012) HLA-Cw*0102-restricted HIV-1 p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function. PLoS Pathog 8:e1002805

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