The long-term objective of the proposed research is to understand molecular mechanisms of HIV-1 pathogenesis. Children receiving highly active antiretroviral therapy [HAART] with the protease inhibitor ritonavir display dramatic immunoreconstitution that produces rapid and sustained three- to ten-fold increases in both memory and naive CD4 T cell subsets. In the majority of children a significant reduction of greater then one log in viral burden accompanied immunoreconstitution, although virus levels were seldom reduced to undetectable. In contrast, about one-third of the children had limited virological response to HAART, even with dramatic immune reconstitution and improvement in clinical course. Genotypic drug resistance developed in viruses that emerged during antiviral therapy independent of changes in virus burden. Other characteristics of post therapy viruses, such as tropism, phenotype, levels of replication, host cell range, and dynamics of genetic variability in regions of the virus genome other than those targeted by the drugs, are not well studied, particularly in the pediatric population, and are the focus of the proposal. Research plan is designed to test the hypothesis that T cell reconstitution is influenced by the viruses, which emerge in response to HAART and are qualitatively different from pretherapy viruses. There are three specific aims: 1. To assess changes in biological phenotype and genetic complexity of M-tropic viruses that emerge in children treated with HAART. 2. To identify interactions between M-tropic viruses and naive or memory CD4 T cells in vivo which are associated with virus levels during HAART. 3. To identify mechanisms which contribute to significant differences in replicative ability of M-tropic viruses by using a novel approach to evaluate interactions between M-tropic virus envelope glycoproteins and chemokine receptors. The research plan includes novel approaches to assess quantitative interactions between viruses and host cells to understand mechanisms of pathogenesis in vivo. Results will provide new parameters that, in addition to viral burden, can be used to evaluate pathogenic potential of viruses that emerge in response to HAART in children and in adults. Factors that serve as predictors of immunoreconstitution are important for assessing the efficacy of HAART, as well as the efficacy strategies designed to augment immunoreconstitution or provide protection from infection.
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