Better understanding of host response to in vivo challenge with HIV may assist the design and evaluation of HIV vaccines. Given uncertainties about host and viral genetic variation across populations, it is important that studies be conducted in the sub-Saharan African populations in which the need for an HIV vaccine is most urgent. This study aims to investigate immunogenetic and virologic factors associated with protection from HIV in the context of perinatal HIV exposure. We plan to recruit a cohort of infants born to HIV-infected mothers in South Africa who have received no antiretroviral drugs before delivery in order to study the development of anti-HIV responses before they may be affected by antiretroviral drugs. These HIV-infected mothers will be identified post-partum and will be offered post-exposure prophylaxis for their infants. Infants will be followed-up to ascertain their infection status. First, the nature of anti-HIV responses in cord blood of infants who escape HIV infection will be investigated using new methods of quantifying antigen-specific intracellular cytokine production by CD4+ and CD8+ T-cells by flow cytometry. Second, attention is focused on interactions between major histocompatibility genes between mother and child, and on the immunologic relevance of these genetic relationships for the development of allogenic and anti-HIV responses which may convey some protection against HIV transmission. Following the hypothesis that fetal contact with foreign maternal histocompatibility antigens in utero may, under certain conditions, help to prevent infection, we plan to measure fetal cord blood lymphocyte reactivity to stimulation with maternal cells, human leukocyte antigen (HLA) genotypes of mother and child, and B-chemokine production and to compare these factors between infected and uninfected infants, and between those with and without anti-HIV responses. We will also investigate whether mutation in maternal virus populations accounts for failure to detect anti-HIV responses in the infant. Since mothers and infants are genetically-related, rare for other routes of HIV transmission, and pregnancy is a unique immunologic circumstance with known trafficking of cells in both directions across the placenta (mother to child, child to mother), maternal-infant HIV transmission offers a distinctive lens through which to attempt to better understand the complexities of potentially protective host immunologic response to HIV.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042402-05
Application #
7100247
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Mofenson, Lynne M
Project Start
2002-09-26
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2009-08-31
Support Year
5
Fiscal Year
2006
Total Cost
$554,707
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Hong, Heather A; Paximadis, Maria; Gray, Glenda E et al. (2015) Maternal human leukocyte antigen-G (HLA-G) genetic variants associate with in utero mother-to-child transmission of HIV-1 in Black South Africans. Infect Genet Evol 30:147-158
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Paximadis, Maria; Minevich, Gregory; Winchester, Robert et al. (2011) KIR-HLA and maternal-infant HIV-1 transmission in sub-Saharan Africa. PLoS One 6:e16541
Tiemessen, Caroline T; Paximadis, Maria; Minevich, Gregory et al. (2011) Natural killer cell responses to HIV-1 peptides are associated with more activating KIR genes and HLA-C genes of the C1 allotype. J Acquir Immune Defic Syndr 57:181-9
Tiemessen, Caroline T; Shalekoff, Sharon; Meddows-Taylor, Stephen et al. (2009) Cutting Edge: Unusual NK cell responses to HIV-1 peptides are associated with protection against maternal-infant transmission of HIV-1. J Immunol 182:5914-8
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Shalekoff, Sharon; Meddows-Taylor, Stephen; Schramm, Diana B et al. (2008) Host CCL3L1 gene copy number in relation to HIV-1-specific CD4+ and CD8+ T-cell responses and viral load in South African women. J Acquir Immune Defic Syndr 48:245-54
Minevich, G; Kuhn, L; Polistena, C et al. (2008) Description of two new HLA-C alleles in a black South African population. Tissue Antigens 71:72-6
Tiemessen, Caroline T; Kuhn, Louise (2007) CC chemokines and protective immunity: insights gained from mother-to-child transmission of HIV. Nat Immunol 8:219-22

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