CCR5 and CXCR4 Binding Chemokines and Oral HIV Infection

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DESCRIPTION (provided by applicant): Oral exposure to HIV-1 accounts for the majority of pediatric HIV-1 infections in developing countries where most HIV-1 infected women breastfeed their babies for cultural and socioeconomic reasons. Identifying factors that protect infants against HIV-1 infection may lead to the development of novel agents to prevent mother-to-child HIV-1 transmission in these settings. Chemokines, the natural ligands for the HIV-1 co-receptors CCR5 and CXCR4, are potential candidates. In vitro studies have demonstrated that CCR5 and CXCR4 binding chemokines inhibit HIV-1 by receptor blockade or downregulation. Clinical studies and studies describing genetic mutations associated with these chemokines also support a role for chemokines in HIV-1 infection and disease progression. The goal of the proposed study is to determine whether the CC and CXC chemokines (MIP-1?, MIP-1?, RANTES, and SDF-1) protect against intrapartum and breastmilk HIV-1 transmission. The proposed study will utilize the infrastructure of an ongoing 5 year NIH-funded perinatal study in Nairobi, the "CTLs and Prevention of Breastmilk HIV-1 Transmission" study. Breastmilk samples from the cohort will be used to determine the association between chemokine levels measured using ELISA and risk of infant HIV-1 infection during 12 months of follow-up. Breastmilk chemokine levels will also be associated with HIV-1 viral load and maternal genotypes for SDF-1, RANTES, and the CCR5 coreceptor. A new cohort of 50 HIV-1 infected and 25 HIV-1 uninfected pregnant women in Nairobi will be recruited to collect additional specimens (maternal blood, breastmilk, cervicovaginal fluid, infant cord blood, infant saliva) in order to characterize chemokine production in more detail. The purpose of this cohort will be to identify those cells responsible for local production of chemokines using intracellular chemokine staining and to define the relationship between chemokine levels in different compartments. Through the collaboration and expertise of scientists in Nairobi, Oxford, and Seattle, the proposed study will provide insight into how chemokines and chemokine analogs may be used to develop innovative therapies to prevent infant HIV-1 infection.