As a consequence of earlier studies of the clinical outcome of HIV- infected children and laboratory studies of pathogenesis, we believe that there are far-reaching consequences of host genetic factors inherited by individuals exposed to HIV. These factors play an early role in determining whether infection occurs and, if it occurs, whether viral replication can be effectively downregulated. Our observations, based on almost ten years of performing natural-history studies, suggest that excessive HIV replication is predictive of a poor clinical outcome and that well-regulated HIV replication early in infancy correlates with a good clinical outcome. Our central hypothesis is that immune- response, gene-mediated responses to HIV regulate viral replication and that these responses appear early in life. This early response may well reflect the ultimate outcome after HIV exposure. These ideas lead us to explore the following specific aims: 1) To examine the nature and interrelationship of genetic, immunologic, and virologic factors that should influence whether children born to infected women will become infected. a: To correlate the presence of MHC class I and/or II alleles with HIV transmission. b: To determine whether high-risk children who avoid HIV-1 infection demonstrate CD4-mediated responses to HIV antigens and whether the presence of these responses is found preferentially in children with MHC class II alleles such as HLA DR13. c: To determine whether 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. d: To determine whether the presence of HIV second receptor (e.g., CCR5, CXCR4, CCR2, etc) mutation or cell-surface density on infant cells is correlated with HIV transmission. 2) Once HIV infection has occurred in exposed infants, to measure their early T-cell-mediated response to HIV, correlate the response with their HLA class I and II MHC, and determine whether the presence of particular responses regulates 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 chronic HIV infection and to determine whether early HIV-1 viremia and/or early host T-cell responses to HIV-1 antigens can be correlated with the outcome. The lab will be utilized for PCR, oligonucleotide synthesis, RNA isolation, and recombinant DNA techniques.
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