Infants of HIV-1 seropositive women have -16% risk of acquiring HIV-1 through breastfeeding. Some uninfected infants born to HIV-1 infected women generate HIV-1 specific cytotoxic T lymphocytes (CTLs), suggesting viral antigenic exposure sufficient to induce immunity but not to establish infection. The cellular component of breast milk contains -10% lymphocytes, which are predominantly CD8+ T cells that may function as CTLs. Therefore, HIV-1 infected women may have virus-specific CTLs in breast milk that contribute to the defense of the neonate. Breast milk HIV-1 specific CTLs may either reduce levels of HIV-1 in breast milk or function as antiviral effector cells in the neonate. Animal models have shown that breast milk cells can survive in the neonatal gut. This proposal aims to identify the correlates and prevalence of HIV-1 specific breast milk CTLs in HIV-1 infected women, to compare CTLs in breast milk to those in blood, and to determine the association of breast milk CTLs with breast milk transmission of HJV-1 and with detection of CTLs in infants. Preliminary studies in 20 HIV-1 infected women show that breast milk contains HIV-1 specific lymphocytes capable of responding to recombinant vaccinia virus expressing either HIV-1- gpl20env or p55gag in gamma interferon ELlSpot assays. The proposed studies will be conducted using specimens obtained as part of an ongoing study in Nairobi. ELlSpot assays (vaccinia HIV-1 env and gag) will be conducted on cryopreserved breast milk specimens from 300 women to determine association of maternal breast milk CTL activity with detection of infant CTLs and risk of infant HIV-l infection in the cohort. In a subset of women, antenatal specimens will be used for HLA typing, and PBMCs obtained at delivery will be stimulated with Class I-restricted peptides to determine immunodominant responses. Paired blood and breast milk specimens at 2 and 4 weeks postpartum will be assessed for viral load, immunophenotyping, and lymphocyte responses to vv-env, vv-gag, and immunodominant peptides identified at delivery. CD8+ lymphocytes from breast milk and blood of a subset of women with high frequency ELlSpot responses (>300 SFU/106 cells) will be further characterized using a panel of peptide-HIA tetramers that have been developed for East African class I molecules and HIV-1 clades. The resulting findings will be relevant to development of vaccines for prevention of mother-to-child transmission of HIV-1.
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