The overall goal of this proposal is to determine the dynamics of virus replication and T cell turnover in HIV-1 infected infants and children. The long-term objective is to determine the impact of combination antiviral drug therapy on T cell regeneration by thymus-dependent and thymus-independent pathways and on the cell reservoir responsible for maintaining covert virus infection. Recent studies from our laboratory show that we can achieve prolonged, durable suppression of viral replication and a reversal of T cell abnormalities and T cell regeneration by thymus dependent mechanisms. Despite suppression of viral replication below the limit of detection, virus persists within infected cells in transcriptionally active but non-productive and latent states. Our objectives are to systematically define the molecular events necessary for establishing and maintaining the initial and subsequent cellular reservoir, the dynamics of replication and cell turnover in each of the relevant tissue compartments, and the state of the viral genome within the infected cell population. We hypothesize that higher numbers of activated target cells, trafficking of early progenitor cells from the thymus, and a developing immature immune system are likely to account for complex differences in the dynamics of plasma virus and infected cell population turnover between children and adults. The potential importance of infection of specific cell populations, through altered virus replication dynamics and cell turnover, provide rationale and motives for studies of viral gene expression, viral latency, and the genetic composition of virus in vivo in virus particles, in defined cell types, and in cellular collections. We will study both infants and children, seeking to determine any age-dependant changes in the thymic renewal mechanisms, and age-related differences in the duration of infection, antiviral drug experience, and control of viral replication after combination antiviral drug therapy. From such data, detailed mathematical analyses similar to those performed on samples from adults can be done that provide a kinetic picture of the mechanisms of compensatory reactivity and expansion of the T cell population and virus production, and into their capacity to respond to antiviral drug therapy. These investigations will provide fundamental insights into the pathogenesis of pediatric HIV-1 infection, and help establish theoretical principles to guide the rationale approach to the development of efficacious treatment strategies.
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