Acquired immunodeficiency syndrome (AIDS) in the pediatric population is an increasingly important problem. The majority of new cases of pediatric human immunodeficiency virus (HIV) infection are the result of perinatal transmission. The clinical course in HIV-infected infants is highly variable--the majority of infants manifest severe immunodeficiency in the first months of life, but others remain symptom-free for years. In adults, cytotoxic T-lymphocytes (CTL) specific for HIV-1 are believed to play an important role in controlling HIV-1 infection during the clinically latent period, but wane with advancing disease. Little is known about the role of HIV-specific CTL's in pediatric AIDS. We propose to characterize the HIV-1-specific CTL responses in infants and children born of HIV-infected mothers using fresh, unstimulated peripheral blood mononuclear cells (PBMC's) as well as by limiting dilution analysis of CTL precursors. HIV-1-specific CTL responses will be compared among infected children at different stages of disease. In addition, virus-specific CTL activity will be followed longitudinally and correlated with events in the child's clinical course. CD8+ HIV-specific CTL clones will be established from the HIV-1-infected mothers of these children and their epitope specificity determined. The ability of these clones to lyse target cells presenting homologous epitopes derived from pediatric HIV-1 isolates will be examined to test the hypothesis that perinatal transmission is mediated by HIV-1 mutants that 'escape', from CTL control. To examine the diversity of the T cell receptor (TCR) repertoire displayed by T cells from HIV-1 infected children, variable beta (Vbeta) region gene usage will be examined by quantitative PCR of Vbeta mRNA and flow cytometry analysis of Vbeta expression at the cell surface in collaboration with Dr. Brian Kotzin.
