T-CELL FUNCTION IN PEDIATRIC AIDS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Maternal transmission of human immunodeficiency virus type 1 (HIV-1) accounts for most cases of pediatric HIV-1 infection. Approximately 75 to 85% of perinatally HIV-1-infected infants develop a slowly progressive course of infection with a slow CD4 decline. In contrast, 10 to 25% of infected infants develop rapidly progressive infection with early CD4+ T-cell depletion followed by death within the first two years of life. The mechanism whereby the first group maintains some control over viral replication is not understood. Previous studies have implicated the role of cytotoxic T lymphocytes, neutralizing antibody and antibody-dependent cellular cytotoxicity in the early control of viral replication in adults, but CD8+ CTL responses in the first six months of HIV infection in infants are rarely observed and anti-HIV antibody responses very limited. Scientists have speculated that susceptibility of children to AIDS is due to the "immaturity of their immune system". However, a variety of ethical and practical considerations inherent in human clinical studies make it difficult to rigorously address these issues in Pediatric AIDS. The goal of this proposal is to use newborn monkeys infected with a pathogenic or non-pathogenic strain of simian immunodeficiency virus (SIV) to carefully define developmental changes in T cells composition and function compared to uninfected na¿ve aged-matched neonates. We will use optimized multiparameter flow cytometry assays to better characterize the early virus-specific T cell responses in SIV-infected newborn macaques. Specific aims include: Specific aim 1: To investigate the dynamics and activation of SIV-specific T lymphocyte responses in early SIV infection in neonatal macaques; to characterize the distribution and frequency of SIV-specific T lymphocytes in specific host tissues; and, to examine if there are any functional impairments of the response Specific aim 2: To develop an oral SIV transmission model in neonate macaques to mimic mother-to-child transmission of HIV-1 to gain a better understanding of mechanisms of oral transmission and mucosal host immune responses in newborns and infants. Understanding why the immune responses fail to clear or control the AIDS infection is important not only to understand the pathogenesis of the disease but also to design appropriates therapeutic interventions. This information should enhance our basic understanding of disease progression and help to understand the immune responses in HIV-infected newborns and infants.