Mathematical modeling combined with experiment has led to increased understanding of the processes that underlie HIV-1 infection in humans and the development of improved therapies. Nevertheless HIV has not been eradicated from infected individuals and various reservoirs including latently-infected cells, virus trapped on folliculary dendritic cells (FDC), and virus in semen have been identified. This application proposes to continue the development of more realistic models of HIV infection with particular emphasis on events that occur in lymphoid tissue. The applicants propose to develop models that explicitly take into consideration infection in blood and tissue, the role of FDC, and possible incomplete penetrance of drugs into various cell populations and tissues. The primary health-related effects of HIV infection are consequences of CD4+ T cell depletion. Nevertheless, the population dynamics of T cells in vivo are poorly characterized. It is proposed to develop theory and analyze data from in vivo labeling studies that will help characterize the rates of proliferation and death of T cells in uninfected, HIV-infected, and HIV-infected individuals under potent antiretroviral treatment. Infection by hepatitis C virus (HCV) and hepatitis B virus (HBV) continue to cause liver failure and hepatocellular carcinoma in many infected individuals. Antiviral therapy for these agents lags behind developments in HIV. The applicants propose to use the modeling and analysis tools that they have developed for HIV to increase understanding of the in vivo kinetics of HCV and HBV infection and the effects of antiviral therapy. In addition to gaining basic understanding, this approach aims to put information into a practical setting, and the applicants hope to interact with clinical groups in the design and evaluation of new treatment protocols.
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