This is an application for the renewal of the R01 grant AI52731 "Innate NKT Cells in HIV Infection" which received a priority score of 136 with a 2.3 percentile, and was first funded in 2002. CDId-restricted natural killer T (NKT) cells are innate immune cells with key immunoregulatory functions. They directly recognize and respond to lipid antigens of bacterial origin and take active part in immune responses against such pathogens. Our studies have shown that the NKT cell compartment is severely compromised by HIV-1 infection, but can be partially restored by treatment with interleukin-2 (IL-2) therapy. In the first specific we will ascertain whether treatment of HIV-1 infected subjects with antiretroviral therapy in combination with IL-2 can induce sustained increases in circulating NKT cell frequency and functions.
We aim to determine the circulating NKT cell frequencies, surface phenotypes, and ex vivo effector functions longitudinally in subjects treated with ART alone or ART in combination with IL-2.
In specific aim 2 we will determine the mechanisms and consequences of CD1d down-regulation in HIV-1 infected dendritic cells.
We aim to determine the mechanism of HIV-1 interference with CD1-mediated antigen presentation, and to investigate the functional consequences of this for NKT cell recognition of glycolipid antigens, and the downstream activation of both the DC and NK cells.
In specific aim 3 we will investigate the relationship between NKT cell loss in HIV-1 infected subjects and the emergence of mycobacterial infections. Our preliminary data suggests that control of Mycobacterium tuberculosis is impaired in HIV-1-uninfected subjects with low levels of circulating NKT cells. We will compare NKT cell frequencies in HIV-1 infected subjects with MTB with age and CD4 T cell count matched controls to determine whether MTB is associated with lower NKT cell frequencies. We will also test whether treatment of MTB is associated with increases in NKT cells to assess whether lower NKT cell counts may be an underlying risk factor for MTB or may represent a sequelae of untreated MTB. We believe that the continued studies we propose will contribute considerably to our understanding of how NKT cells function in HIV-1 disease, how the virus attempts to escape NKT cell activation, and how they may contribute to the innate defense against HIV-1 infection and AIDS-defining opportunistic infections.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI052731-15
Application #
8687575
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Stansell, Elizabeth H
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
George Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
Paquin-Proulx, Dominic; Gibbs, Anna; Bächle, Susanna M et al. (2016) Innate Invariant NKT Cell Recognition of HIV-1-Infected Dendritic Cells Is an Early Detection Mechanism Targeted by Viral Immune Evasion. J Immunol 197:1843-51
Bächle, Susanna M; Malone, David F G; Buggert, Marcus et al. (2016) Elevated levels of invariant natural killer T-cell and natural killer cell activation correlate with disease progression in HIV-1 and HIV-2 infections. AIDS 30:1713-22
Paquin-Proulx, D; Ching, C; Vujkovic-Cvijin, I et al. (2016) Bacteroides are associated with GALT iNKT cell function and reduction of microbial translocation in HIV-1 infection. Mucosal Immunol :
Crisci, Elisa; Ellegård, Rada; Nyström, Sofia et al. (2016) Complement Opsonization Promotes Herpes Simplex Virus 2 Infection of Human Dendritic Cells. J Virol 90:4939-50
Bächle, Susanna M; Sauter, Daniel; Sibitz, Sabrina et al. (2015) Involvement of a C-terminal motif in the interference of primate lentiviral Vpu proteins with CD1d-mediated antigen presentation. Sci Rep 5:9675
Carpenter, Chelsea; Sidney, John; Kolla, Ravi et al. (2015) A side-by-side comparison of T cell reactivity to fifty-nine Mycobacterium tuberculosis antigens in diverse populations from five continents. Tuberculosis (Edinb) 95:713-21
Leeansyah, Edwin; Loh, Liyen; Nixon, Douglas F et al. (2014) Acquisition of innate-like microbial reactivity in mucosal tissues during human fetal MAIT-cell development. Nat Commun 5:3143
Tjomsland, Veronica; Ellegård, Rada; Burgener, Adam et al. (2013) Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells. Eur J Immunol 43:1470-83
Andersson, Sofia K; Paquin-Proulx, Dominic; Kroll, Mirko et al. (2013) Technical advance. Measurement of iNKT cell responses at the single-cell level against rare HIV-1-infected dendritic cells in a mixed culture. J Leukoc Biol 93:449-55
Paquin-Proulx, Dominic; Santos, Bianca A N; Carvalho, Karina I et al. (2013) Dysregulated CD1 profile in myeloid dendritic cells in CVID is normalized by IVIg treatment. Blood 121:4963-4

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