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 #
5R01AI067031-08
Application #
8485508
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Lawrence, Diane M
Project Start
2005-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$408,900
Indirect Cost
$173,900
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
K├Ârner, Christian; Granoff, Mitchell E; Amero, Molly A et al. (2014) Increased frequency and function of KIR2DL1-3? NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes. Eur J Immunol 44:2938-48
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; O'Connor, Geraldine M; Kumar, Swati et al. (2011) Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules. J Virol 85:5970-4
Alter, Galit; Altfeld, Marcus (2011) Mutiny or scrutiny: NK cell modulation of DC function in HIV-1 infection. Trends Immunol 32:219-24
Alter, Galit; Heckerman, David; Schneidewind, Arne et al. (2011) HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476:96-100
Nolting, Anne; Dugast, Anne-Sophie; Rihn, Suzannah et al. (2010) MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction. Virology 406:12-20
Alter, G; Altfeld, M (2009) NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J Intern Med 265:29-42
Alter, Galit; Rihn, Suzannah; Walter, Katharine et al. (2009) HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection. J Virol 83:6798-805
Zucchini, Nicolas; Crozat, Karine; Baranek, Thomas et al. (2008) Natural killer cells in immunodefense against infective agents. Expert Rev Anti Infect Ther 6:867-85
Meier, Angela; Alter, Galit; Frahm, Nicole et al. (2007) MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81:8180-91

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