Among infants born to HIV+ mothers, some but not all become infected themselves. During the current period of this project, we have demonstrated that an exposed infant's genotype at critical immune response loci (the HLA class II region) appears to influence the infant's risk of perinatal HIV infection. In the upcoming three years, we propose, first, to study this association further by identifying the exact sequence(s) in the HLA region responsible for influencing susceptibility to perinatal infection. The role of genotypes of the variable and constant regions of the alpha and beta chains of T-cell receptors, which interact with HLA molecules, will also be evaluated. Second, enough infected mothers of exposed infants are now being enrolled in follow-up cohorts in San Francisco and New York to permit evaluation of maternal genetic risk factors for transmission. The same genes will be tested among the mothers. Third, we will test whether the genotype of an HIV+ infant influences the rate of disease progression and/or the nature of symptoms that develop. Finally, new molecular techniques permit us to identify genetic variation in HIV itself. We will explore both whether the HIV genotype(s) carried by the mother influence her transmission of the virus; and whether the HIV genotype of an infected infant influences the rate and nature of disease progression. Study design will be case-control drawn from three prospective cohorts. New subjects from New York City will include approximately 550 infants born to infected women delivering at Harlem Hospital or Bronx-Lebanon Hospital and enrolled in the NYC and CDC follow-up cohorts, respectively, as well as approximately 194 of their infected mothers. Subjects from the BAPAC cohort in San Francisco will include approximately 105 infants and the infected mother of each infant. Combined with subjects already in our series, our ultimate sample size will be approximately 930 exposed infants and 323 of their infected mothers. Approximately 371 infants will be HIV+ and 566 HIV- despite perinatal exposure. This sample size should be sufficient for analyses stratified by ethnicity and some evaluation of interactions of host genotype x HIV genotype x outcome.
