An estimated 7-40% of infants born to HIV-1-infected mothers will ultimately be shown to be infected with this retrovirus. Although both humoral and cellular HIV-1-specific immune responses have been identified in infected persons, the potential role of specific maternal immune responses in preventing vertical and/or perinatal transmission of this infection has not been established conclusively. The goal of this proposal is to perform a detailed analysis of both humoral and cellular HIV-1-specific immune responses in infected pregnant mothers which may protect from or facilitate mother-to-child virus transmission. To this end, we have established a collaboration among investigators at Massachusetts General Hospital (MGH) with expertise in cellular HIV-1-specific immunity, at Repligen Corporation with expertise in humoral HIV-1-specific immunity, and at Boston City Hospital (BCH), with expertise in the evaluation and clinical care of HIV-1-infected pregnant mothers and neonates. Specifically, we propose to: 1) Characterize the HIV-1-specific cytotoxic T lymphocyte (CTL) response in infected pregnant mothers and identify the CTL epitopes recognized, 2). Investigate the ability of CD8+ lymphocytes from infected pregnant mothers to inhibit autologous virus replication in PBMC, 3) Quantitatively assess the ability of maternal serum antibodies to neutralize maternal and neonatal virus isolates, 4).Identify the specific humoral epitopes recognized by maternal antibodies which are responsible for neutralization of maternal and neonatal virus isolates, 5) Expand these studies to investigate the role of cellular and humoral HIV- I -specific immunity in modulating disease in infants born to seropositive mothers. By studying these parameters in the same cohort of patients, we hope to establish whether HIV-1-specific cellular immunity and/or HIV-1-- specific humoral immunity modulate disease transmission from mother to child. These studies should provide important information regarding the immunopathogenesis of vertical HIV-1 transmission, and may help in the rational design of immunomodulatory therapies.
