An in depth research experience is planned to enhance and broaden the candidate's expertise in developmental cellular immunology. The training will take place in the laboratory of Dr. Robert Schooley, a leading investigator in the field of immune responses to and immune-based therapies for HIV. The research plan builds on the candidate's prior research endeavors and extends those experiences to include additional experimental techniques to permit the candidate to develop a well-rounded capability to study multiple aspects of immune cytotoxicity and cytokine function. HIV-specific cytotoxic T-lymphocytes (CTL) are readily demonstrated in peripheral blood mononuclear cell (PBMC) obtained from the majority of HIV-infected adults without a requirement for in vitro stimulation and are associated with slower disease progression in adults. By contrast, activated HIV-specific CTL in circulating PBMC are observed less frequently in infants and children with vertically-acquired HIV-infection. However, we and others have demonstrated the presence of HIV-specific precursor CTL (pCTL) in PBMC at high frequencies in the majority of HIV- infected children. Although the factors required for activation of CTL are not fully understood, our hypothesis is that the cell-mediated immune deficits described in the fetus and newborn may result in a deficient immune defense against HIV in the setting of maternal transmission. Interleukin-12 (IL-12) is a cytokine which stimulates CD3-mediated cytotoxicity, natural killer (NK) activity and gamma-interferon production in PBMC from adults. Each of these immune functions has been demonstrated to be deficient in newborns. To date no studies of the effects of IL-12 on CTL specific for HIV have been reported. Furthermore, the effects of IL-12 on cytotoxic activity of PBMC in normal or HIV-infected infants and children have not been evaluated. We propose to investigate the ability of IL-12 to enhance HIV-specific CTL and NK activity in children born of HIV-infected mothers. Moreover, we will investigate the ability of neonatal PBMC to produce and respond to IL-12 in comparison to adult PBMC. When enhanced cytolytic activity is observed following stimulation of IL- 12, the mechanisms of action will be evaluated. Determining factors that contribute to activation of these HIV-specific pCTL in vitro may lead to therapeutic strategies for augmenting immune responses in these children. Further, the investigation may lead to increased understanding of the immunologic immaturity of the newborn, hence providing insights into potential approaches to reduce the severity of infections and improve responses to vaccines in this age group.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (SRC (EM))
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Nugent, Robert
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University of Colorado Denver
Schools of Medicine
United States
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McFarland, E J; Harding, P A; MaWhinney, S et al. (1998) In vitro effects of IL-12 on HIV-1-specific CTL lines from HIV-1-infected children. J Immunol 161:513-9