Despite the recent progress, each day approximately 1,600 children become HIV infected, the vast majority of these infections occur in Africa. One-third to one-half of these perinatal HIV infections is due to breast-feeding. Formula feeding is not an option due to economic and cultural imperatives, and because it is often not safe in environments with out access to clean water. For the near term, an enhanced understanding of the factors that contribute to breast milk transmission is essential to help devise appropriate and sustainable efforts to minimize MTCT of HIV in developing countries. The role that potential determinants play on breast milk transmission remains unclear. This proposal will employ a large and well-organized cohort of breast-feeding HIV infected women, the Zambian Exclusive Breast-feeding Study (ZEBS). We will characterize important aspects of HIV breast milk transmission with respect to the virologic and immunologic constitution of breast milk and with respect to the role of local inflammatory disease. The first specific aim of this proposal is to characterize HIV variants in breast milk. We hypothesize that the breast milk is a distinct virologic compartment. We will use HTA and clonal sequencing to establish prevalence and source (i.e. plasma vs.cells) of viral co-mingling between these compartments. Differentially expressed bands will be identified, cloned and sequenced.
The second aim i s determine the effects of mastitis on the HIV quasispecies. Substantial evidence points to an important role oft mastitis in enhancing HIV transmission. Few data exist on the mechanism of this effect on transmission risk. Does it simply increase the population of existing variants or does it produce novel variants that are less subject to immune clearance? We hypothesize that inflammatory cytokines reactivate latent ancestral variants and increase local production. This not only increases viral diversity, resulting a higher probability of a """"""""transmissible strain"""""""" but also may select for variants that have escaped ongoing immune surveillance. We will use HMA/HTA as well as clonal sequencing and phylogenetic analysis to define the changes induced by inflammation.
The final aim i s characterize HIV specific T cell responses in lactating women. We hypothesize that, as in blood, CTL responses play a critical role in HIV suppression. We will assess breast milk CTL response in comparison to blood. These data will be correlated with levels of HIV in both compartments. These studies will provide the foundation for further studies correlating CTL and MTCT and will provide important immune correlates of MTCT.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD040777-01A2
Application #
6496142
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Read, Jennifer
Project Start
2002-07-05
Project End
2006-06-30
Budget Start
2002-07-05
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$363,535
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Lombardi, Francesca; Nakamura, Kyle J; Chen, Thomas et al. (2015) A Conserved Glycan in the C2 Domain of HIV-1 Envelope Acts as a Molecular Switch to Control X4 Utilization by Clonal Variants with Identical V3 Loops. PLoS One 10:e0128116
Kuhn, Louise; Kim, Hae-Young; Hsiao, Lauren et al. (2015) Oligosaccharide composition of breast milk influences survival of uninfected children born to HIV-infected mothers in Lusaka, Zambia. J Nutr 145:66-72
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Tobin, Nicole H; Aldrovandi, Grace M (2014) Are infants unique in their ability to be ""functionally cured"" of HIV-1? Curr HIV/AIDS Rep 11:1-10
Nakamura, Kyle J; Cerini, Chiara; Sobrera, Edwin R et al. (2013) Coverage of primary mother-to-child HIV transmission isolates by second-generation broadly neutralizing antibodies. AIDS 27:337-46
Chan, Christina S; Kim, Hae-Young; Autran, Chloe et al. (2013) Human milk galectin-3 binding protein and breast-feeding-associated HIV transmission. Pediatr Infect Dis J 32:e473-5
Semrau, Katherine; Kuhn, Louise; Brooks, Daniel R et al. (2013) Dynamics of breast milk HIV-1 RNA with unilateral mastitis or abscess. J Acquir Immune Defic Syndr 62:348-55
Mild, Mattias; Gray, Rebecca R; Kvist, Anders et al. (2013) High intrapatient HIV-1 evolutionary rate is associated with CCR5-to-CXCR4 coreceptor switch. Infect Genet Evol 19:369-77

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