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).

R01HD041361

2002-02-20

2007-01-31