Exposure to HIV-1 occurs in all children born to HIV-infected mothers, yet a minority become infected. When HIV infection occurs, a spectrum of clinical outcomes is seen, from rapid disease progression on one end to a process of symbiosis on the other. The factors responsible for whether infection occurs and what disease is produced as a result of infection are likely to be multifactorial. To evaluate HIV pathogenesis, requires performing assays which measure viral replication and diversification, and correlating these with cell-mediated immune responses to HIV, perhaps dictated by HLA genes. The central hypothesis is that immune-response gene-mediated responses to HIV attack regulate viral replication and appear in the first year of life. This early reaction may well reflect the ultimate outcome after HIV exposure. The proposed experiments explore the hypotheses that 1) MHC- defined alleles in the child predict which individual will become infected and, if infection occurs, 2) these alleles also shape clinical outcome. These alleles may well function in both settings by establishing the threshold for initiating HIV-specific immune responses present in the child. Testable hypotheses include 1)'high responder' genotypes will result in an immune response allowing for the elimination of small inocula of HIV-1; and 2) T cells from 'low responder' individuals will fail to do so, resulting in infection. 'High responder' children may still become infected if challenged by exposure to large amounts of virus. 'Low responder' infected children will continue to make inadequate immune responses to HIV, resulting in unrestricted replication seen early in life and immune attrition. In contrast, 'high responder' infected children will mount T cell mediated responses to HIV which, although unable to clear virus, are capable of restricting HIV replication early in life reserving immune cells and maintaining clinical homeostasis. The following aims are proposed: 1) To examine the nature and interrelationship of genetic, immunologic, and virologic factors which should influence whether children born to infected women will become infected and to a) correlate the presence of MHC alleles with HIV transmission; b) determine whether uninfected children demonstrate CD4-mediated responses to HIV antigens and whether these responses are found preferentially in children with MHC class alleles such as HLA DR13; and c) determine whether the failure to avoid infection in those minority of individuals who are HLA DR13+ is a function of exposure to high levels of maternal viremia or the presence of syncytia-inducing (SI) HIV. 2) Once HIV infection has occurred, to measure early T cell-mediated response to HIV, correlate the response with their HLA class I and II alleles, and determine whether the presence of particular responses regulate viral replication, diversification, and phenotype. 3) To assess the early host T cell receptor (TCR) repertoire in the HIV-infected infant and to determine whether any observed skewing in the repertoire is a consequence of HIV-1 replication and/or immune responses to HIV. 4) To assess the clinical outcome of children with HIV infection and determine whether early HIV-1 viremia and/or the early host T cell responses can be correlated with the outcome in a multivariate analysis.
