Maternal-to-child transmission (MTCT) of HIV-1 accounts for up to 500 infected children per year in the U.S. and up to 1,500 infected children per day worldwide. The risk for pre- and perinatal MTCT may be reduced by Caesarian section and anti-retroviral therapy. However, these effective but transient perinatal interventions will have minimal impact on the estimated 25-44 percent of vertical transmission that occurs postnatally through breast-feeding, particularly in sub-Saharan Africa. The early beneficial effects of perinatal antiretroviral therapy on MTCT may be negated by subsequent postnatal infection by breast milk. Indeed, the risk of HIV-1 infection by breastfeeding is approximately 3-10 percent per year. Although breastfeeding carries the risk of HIV-1 transmission, mortality at 24 months is similar in breastfed and non-breastfed children of HIV-1-infected women. As a result, recommendations from international agencies about breastfeeding for HIV-1-infected mothers in resource-poor nations have been controversial and are in evolution. In this context, the timing of postnatal HIV-1 transmission is particularly relevant to the survival of the child. The overall survival benefit of breastfeeding appears to be greatest in the first 6 weeks-6 months. This critical early period may also support the highest rates of HIV-1 transmission. However, reliable determinations of these early rates are confounded by the difficulty of differentiating perinatal from early postnatal exposure. During these intervals, the factors that determine the efficiency of mucosal transmission of HIV-1 by breast milk are poorly characterized. These factors may include 1) HIV-1 concentrations, 2) the transient expression of innate immune factors, and 3) the persistence of acquired immune factors (e.g., HIV-1-specific IgA and IgG). We propose to focus on the functional HIV-1-inhibitory activities of breast milk in vitro as critical determinants of postnatal transmission of HIV-1 by breast milk in vivo and as potential instruments of its prevention. Hypotheses: 1) The functional HIV-1-inhibitory activity of breast milk against autologous HIV-1 isolates predicts protection against postnatal maternal-to-child transmission of HIV-1 by maternal milk in Africa. 2) Acquired immune factors (HIV-1-specific antibodies) in breast milk are the primary determinants of HIV-1 inhibition later in the post-partum period (>6 weeks) 3) Innate immune factors in breast milk are the primary determinants of HIV-1 inhibition in the early post-partum period (< 6 weeks).

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041361-02
Application #
6622579
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Read, Jennifer
Project Start
2002-02-20
Project End
2007-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
2
Fiscal Year
2003
Total Cost
$333,878
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
McFarland, Elizabeth J; Powell, Tina M; Onyango-Makumbi, Carolyne et al. (2017) Ontogeny of CD4+ T Lymphocytes With Phenotypic Susceptibility to HIV-1 During Exclusive and Nonexclusive Breastfeeding in HIV-1-Exposed Ugandan Infants. J Infect Dis 215:368-377
Gaensbauer, James T; Rakhola, Jeremy T; Onyango-Makumbi, Carolyne et al. (2014) Impaired haemophilus influenzae type b transplacental antibody transmission and declining antibody avidity through the first year of life represent potential vulnerabilities for HIV-exposed but -uninfected infants. Clin Vaccine Immunol 21:1661-7
Janoff, E N; Rubins, J B; Fasching, C et al. (2014) Pneumococcal IgA1 protease subverts specific protection by human IgA1. Mucosal Immunol 7:249-56
Aizire, Jim; McConnell, Michelle S; Mudiope, Peter et al. (2012) Kinetics of nevirapine and its impact on HIV-1 RNA levels in maternal plasma and breast milk over time after perinatal single-dose nevirapine. J Acquir Immune Defic Syndr 60:483-8
Frank, Daniel N; Manigart, Olivier; Leroy, Valériane et al. (2012) Altered vaginal microbiota are associated with perinatal mother-to-child transmission of HIV in African women from Burkina Faso. J Acquir Immune Defic Syndr 60:299-306
Vacharaksa, Anjalee; Asrani, Anil C; Gebhard, Kristin H et al. (2008) Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells. Retrovirology 5:66
Mantis, Nicholas J; Palaia, Jana; Hessell, Ann J et al. (2007) Inhibition of HIV-1 infectivity and epithelial cell transfer by human monoclonal IgG and IgA antibodies carrying the b12 V region. J Immunol 179:3144-52
Fasching, Claudine E; Grossman, Tracy; Corthesy, Blaise et al. (2007) Impact of the molecular form of immunoglobulin A on functional activity in defense against Streptococcus pneumoniae. Infect Immun 75:1801-10
Cinova, Jana; Palova-Jelinkova, Lenka; Smythies, Lesley E et al. (2007) Gliadin peptides activate blood monocytes from patients with celiac disease. J Clin Immunol 27:201-9
Maheshwari, Akhil; Smythies, Lesley E; Wu, Xiaoyun et al. (2006) Cytomegalovirus blocks intestinal stroma-induced down-regulation of macrophage HIV-1 infection. J Leukoc Biol 80:1111-7

Showing the most recent 10 out of 22 publications