HIV-1 disease is a serious international health problem and a major cause of death in sub-Saharan Africa. Therapeutic and preventative treatments are limited in availability and effectiveness, thus critical evaluations of alternative approaches to control this virus are greatly needed. The overall goal of this project is to elucidate the mechanisms underlying naturally occurring protective immunity to HIV-1 disease in sub- Saharan Africa.
The specific aims are (1) to determine the role of NK-cells in decreasing mother to child HIV- 1 transmission and in slowing HIV-1-disease progression to AIDS in adults and (2) to determine the molecular mechanisms of HLA-Bw4 80! mediated protection from HIV transmission and disease progression. In the first aim we will conduct a cross-sectional study by collecting peripheral blood samples from mothers who are HIV-transmitters versus non-transmitters and assessing their NK-cell responses to HIV-infected self and child-derived T cells by the production of anti-viral soluble factors (e.g., interferon-y, MIP-1a &(3, and RANTES) as well as by cell-killing assays. We will also conduct a similar analysis with blood samples from HIV-1-infected adults that are virus controllers compared to virus non-controllers. To address the second aim we will generate reporter cells expressing NFAT-LacZ and the NK cell receptor, KIR3DS1. We will assess HLA-B recognition by KIR3DS1 by in vitro co-culture assays with HIV-1 infected and uninfected target cell lines expressing the putative ligand, HLA-B57. To probe molecular mechanisms of recognition by KIR3DS1 further, HLA mutagenesis or HIV peptide screening will be employed. The research plan is ideal for the career objective of the candidate, William Carr, to become an independent investigator in international health research, specializing in innate viral immunity. The proposed career development plan will consist of closely mentored basic-science research with Drs. Marcus Altfeld and Bruce Walker as mentors in the U.S. and Drs. Hoosen Coovardia and Salim Abdool Karim as a mentors in South Africa, state-of-the-art research facilities at the Doris Duke Research Center in Durban, South Africa, and at the Partners AIDS Research Center at Massachusetts General Hospital in the U.S., and a didactic curriculum on ethics in international research. This plan is well suited for Dr. Carr to establish long-term scientific collaborations in South Africa and to establish himself as an independent investigator in international health research

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01TW007793-04
Application #
8010205
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (50))
Program Officer
Jessup, Christine
Project Start
2007-12-01
Project End
2012-03-31
Budget Start
2010-12-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2011
Total Cost
$122,332
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Naranbhai, V; de Assis Rosa, D; Werner, L et al. (2016) Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women. BMC Infect Dis 16:27
Naranbhai, Vivek; Hill, Adrian V S; Abdool Karim, Salim S et al. (2014) Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy. J Infect Dis 209:500-9
Naranbhai, Vivek; Chang, Christina C; Durgiah, Raveshni et al. (2014) Compartmentalization of innate immune responses in the central nervous system during cryptococcal meningitis/HIV coinfection. AIDS 28:657-66
Apalata, Teke; Carr, William H; Sturm, Willem A et al. (2014) Determinants of symptomatic vulvovaginal candidiasis among human immunodeficiency virus type 1 infected women in rural KwaZulu-Natal, South Africa. Infect Dis Obstet Gynecol 2014:387070
Naranbhai, Vivek; Samsunder, Natasha; Sandler, Netanya G et al. (2013) Neither microbial translocation nor TLR responsiveness are likely explanations for preexisting immune activation in women who subsequently acquired HIV in CAPRISA 004. J Acquir Immune Defic Syndr 63:294-8
Naranbhai, Vivek; Altfeld, Marcus; Karim, Salim S Abdool et al. (2013) Changes in Natural Killer cell activation and function during primary HIV-1 Infection. PLoS One 8:e53251
Naranbhai, Vivek; Altfeld, Marcus; Abdool Karim, Quarraisha et al. (2012) Natural killer cell function in women at high risk for HIV acquisition: insights from a microbicide trial. AIDS 26:1745-53
Naranbhai, Vivek; Abdool Karim, Salim S; Altfeld, Marcus et al. (2012) Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. J Infect Dis 206:993-1001
Ndlovu, B G; Danaviah, S; Moodley, E et al. (2012) Use of dried blood spots for the determination of genetic variation of interleukin-10, killer immunoglobulin-like receptor and HLA class I genes. Tissue Antigens 79:114-22
Hong, H A; Loubser, A S; de Assis Rosa, D et al. (2011) Killer-cell immunoglobulin-like receptor genotyping and HLA killer-cell immunoglobulin-like receptor-ligand identification by real-time polymerase chain reaction. Tissue Antigens 78:185-94

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