The objective of the proposal is to study the role of HIV-1 specific cytotoxic T cells in pathogenesis of vertical HIV infection. The hypothesis is that the role of HIV-1 specific CTL in controlling viremia and protecting against disease progression following vertical infection is dependent not only on the timing of detection, magnitude, and breadth of HIV-1 specific CTL responses, but also on their functional properties in rapid and slow progressors, and that HIV-1 specific CTL will be detected later and at lower frequencies in RP than in SP. The preliminary results suggest, however, that some HIV-1 infected infants may experience RP despite an apparently vigorous and broad CTL response. The principal investigator will therefore also examine the functional properties of CTL in RP and SP. Using a cohort of infants with well-defined laboratory parameters (viral load, CD4 counts), the principal investigator aims to serially quantify peripheral blood HIV-specific CTL precursors (CTLp) frequencies. The time to detection of CTLp, changes of CTLp over time, and the relationship between CTLp frequencies and blood viral load will be examined and compared in infants with rapid or slow disease progression. Next, the investigators will generate HIV-specific CTL clones from selected RP and SP in order to identify epitopes recognized and HLA restricting elements. Finally, functional properties of the HIV-specific clones from RP and SP (ability to recognize variant peptides, cytokine secretion patterns, and ability to lyse or to control HIV replication in naturally-infected CD4 T cells) will be examined. The proposed studies are important in understanding the pathogenesis of vertical HIV-1 infection and for the development of a vaccine to interrupt vertical infection
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