Abstract

Innate immunity is the first line of defense designed to protect the host from invading pathogens, including HIV. HIV viremia is associated with a wide range of immune dysfunctions that contribute to an immunocompromised state and disease progression. Persistent HIV replication has been shown to have a broad effect on several immune cell types and/or their interactions involved in mounting an effective immune response. We have previously described several NK cell abnormalities in HIV-viremic individuals. In the past year, we investigated the integrity of plasmacytoid dendritic cell (pDC)-NK cell interactions among HIV viremic, aviremic and seronegative individuals. Our results describe: 1) a critical defect in the ability of pDCs from HIV infected individuals to secrete IFN- and TNF and subsequently activate NK cells and: 2) an inherent defect in NK cells from HIV infected individuals to respond to pDC-secreted cytokines. Furthermore, we were able to demonstrate a direct effect of HIV trimeric gp120 on NK cells in vitro similar to that described ex vivo. Finally, we were able to establish that HIV gp120-mediated suppressive effect on NK cells resulted from its binding to the integrin alpha4beta7 expressed on NK cells. These findings suggest a novel mechanism by which HIV is capable of suppressing innate immune function in infected individuals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000886-08
Application #
7732559
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2008
Total Cost
$836,377
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Kottilil, Shyam; Yan, Michael Y; Reitano, Kristin N et al. (2009) Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells. Hepatology 50:34-45
Chun, Tae-Wook; Nickle, David C; Justement, Jesse S et al. (2008) Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 197:714-20
Cortez, Karoll J; Roilides, Emmanuel; Quiroz-Telles, Flavio et al. (2008) Infections caused by Scedosporium spp. Clin Microbiol Rev 21:157-97
Moir, Susan; Malaspina, Angela; Ho, Jason et al. (2008) Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. J Infect Dis 197:572-9
Tilton, John C; Manion, Maura M; Luskin, Marlise R et al. (2008) Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro. J Virol 82:3997-4006
Arthos, James; Cicala, Claudia; Martinelli, Elena et al. (2008) HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 9:301-9
Neumann, Au; Polis, Ma; Rozenberg, L et al. (2007) Differential antiviral effect of PEG-interferon-alpha-2b on HIV and HCV in the treatment of HIV/HCV co-infected patients. AIDS 21:1855-65
Meyers, Jennifer Hartt; Justement, J Shawn; Hallahan, Claire W et al. (2007) Impact of HIV on cell survival and antiviral activity of plasmacytoid dendritic cells. PLoS ONE 2:e458
Malaspina, Angela; Moir, Susan; Chaitt, Doreen G et al. (2007) Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood 109:2086-8
Kottilil, Shyam; Jackson, Julia O; Reitano, Kristin N et al. (2007) Innate immunity in HIV infection: enhanced susceptibility to CD95-mediated natural killer cell death and turnover induced by HIV viremia. J Acquir Immune Defic Syndr 46:151-9

Showing the most recent 10 out of 28 publications