Mathematical modeling combined with experimentation has led to the increased understanding of the processes that underlie HIV-1 infection in humans. By analyzing experiments in which potent antiretroviral agents were used to perturb patients whose viral loads were in quasi-steady state, the Principal Investigator and his associates, were able to determine that HIV replication occurs at high rates in infected people. Comparing experimental data with mathematical models these researchers concluded that in the average HIV patient at least 10 billion virions are produced, released into the extracellular fluid, and cleared per day. Further, the half-live (t1/2) of free virions in plasma was estimated to be 6 hours or less, and that the cells, presumably CD4+ T Cells, responsible for 93-99% of the steady state viral production have a t1/2 of 1.6 days or less. The remaining virions appear to be produced by a longer-lived compartment that decays with a t1/2 of between 1 and 4 weeks. In this application, the Investigator proposes a variety of studies aimed at extending our understanding of viral and lymphocyte dynamics, and the evolution of drug resistance. Specifically, the Investigator proposes: (1) to relax the assumptions upon which our current estimates of the rate of virion clearance and the t1/2 of productively infected cells were based--that antiviral therapy is 100% effective and that the increase in target cell numbers can be ignored--and study the consequences; (2) to extend our modeling and analysis to virions and lymphocytes in both blood and lymphoid tissue, and analyze explicitly the trapping of virions on follicular dendritic cells; (3) to develop models that consider explicitly the possibility of drug resistant virions pre-existing treatment and/or arising by mutation during antiviral therapy and to examine the conditions under which virus might be eradicated or maintained at low levels by continued therapy; and (4) to examine the population dynamics of T cells within patients both before and during antiviral therapy to help elucidate the roles of cell proliferation, apoptosis, de novo generation of naive cells, and cell trafficking in observed recovery of T lymphocytes. In addition to gaining basic understanding the Investigator proposes putting this information into a practical setting, and to interact with clinical groups in the design and evaluation of new treatment protocols.
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