The goal of this project is to test whether host genotype may contribute to infant susceptibility to HIV infection or to likelihood of maternal transmission of HIV. Transmission of HIV from mothers to their children during Pregnancy is one of the least understood but most pressing research areas in the AIDS field. To help address this problem, we propose to integrate molecular genetic analysis into in existing, major epidemiologic and virologic investigation of prenatal/perinatal new infection at St. Luke's/Roosevelt Hospital in New York City. At this hospital, ~4% of infants are born to HlV-infected mothers. Of these infants, 25-40% will have been infected with HIV, whereas 60-75% remain uninfected. We will compare ~40 infected infants to ~ 80 uninfected infants of HIV seropositive mothers with respect to genotypes of sequences potentially related to HIV infection and immune response. The goal is to test whether the host genotype of the exposed infant influences susceptibility to infection. We will also compare ~40 infected mothers who transmit HIV prenatally with ~80 infected-but-not-transmitting mothers with respect to genotypes in immune response sequences. The goal of this comparison is to test whether maternal genotype influences transmissibility of HlV. Candidate genes include HLA B, DR, and DQ; T-cell antigens T4 and T8; interleukin 2; interferons alpha, beta, beta 2, and gamma; immunoglobulins; and T-cell receptor alpha, beta, and gamma chains. We currently screen these sequences by hybridization with probes that reveal restriction enzyme polymorphism, and increasingly, by polymerase amplification followed by hybridization to allele- specific oligonucleotide. These techniques enhance detection of polymorphism, thereby increasing statistical power, an essential factor in working with necessarily small sample sizes. Genetic data will be integrated with extensive clinical, epidemiological and virological information (which is already being collected concerning severity of maternal disease during pregancy and other charscteristics of the mother, the pregnancy, and the viens, that might influence the likelihood of HIV transmission to the fetus. If host genotype contributes either to susceptibility to infection or to transmissibility, identification of the genes involved would be important in understanding the infective process and to development of therapeutic interventions.
