Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067031-10
Application #
8890737
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
2015-07-01
Budget End
2016-06-30
Support Year
10
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code

  Publications

Körner, Christian; Simoneau, Camille R; Schommers, Philipp et al. (2017) HIV-1-Mediated Downmodulation of HLA-C Impacts Target Cell Recognition and Antiviral Activity of NK Cells. Cell Host Microbe 22:111-119.e4
Lunemann, Sebastian; Martrus, Gloria; Hölzemer, Angelique et al. (2016) Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to HLA-C?03:04 and modulate NK cell function. J Hepatol 65:252-8
Martrus, Glòria; Altfeld, Marcus (2016) Immunological strategies to target HIV persistence. Curr Opin HIV AIDS 11:402-8
He, Xuan; Simoneau, Camille R; Granoff, Mitchell E et al. (2016) Assessment of the antiviral capacity of primary natural killer cells by optimized in vitro quantification of HIV-1 replication. J Immunol Methods 434:53-60
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
Reeves, R Keith; Li, Haiying; Jost, Stephanie et al. (2015) Antigen-specific NK cell memory in rhesus macaques. Nat Immunol 16:927-32
Altfeld, Marcus; Gale Jr, Michael (2015) Innate immunity against HIV-1 infection. Nat Immunol 16:554-62
Körner, 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
Jost, Stephanie; Altfeld, Marcus (2012) Evasion from NK cell-mediated immune responses by HIV-1. Microbes Infect 14:904-15

Showing the most recent 10 out of 20 publications