This OIG renewal proposal is to continue our studies on the human immunodeficiency viruses types 1 and 2 (HIV-1, HIV-2), the human T cell leukemia viruses types 1 and 2 (HTLV-1, HTLV-2), the human hepatitis B virus )HBV), and the human hepatitis delta virus (HDV). In all cases, emphasis will be on the mechanisms by which the viruses induce disease and the mechanisms of transmission of the viruses. In the cases of HIV-1 we will continue our analysis of the envelope gp120 to determine which epitopes and domains are most important in a functional sense for natural resistance, for vaccine development, and for diagnosis of stage of disease progression or prognosis. Glycosylation sites and disulfide bonds will also be analyzed and new viral proteins will be mapped. Mechanisms by which HIV's cause immunosuppression at the cellular and host level will also be determined. Epidemiological and biological studies will be conducted with HIV-2 to determine the relative virulence and pathogenicity of this virus as compared to HIV-1. The comparative studies will include cell tropism and virus replication load, efficiency of transmission between individuals and between cells in the same person, natural immunogenicity, and role and efficiency of several HIV-2 regulatory genes as compared to HIV-1 regulatory genes. The pathogenesis and epidemiology of HTLV-1 and HTLV-2 will also be analyzed in relation to development of adult T cell leukemia (ATL) and other clinical outcomes. The role of env, tax, rex, and other viral proteins and their domains and representative antibodies will be evaluated for diagnostic prognostic, and transmissibility determinations. The tropism of HTLV's will be analyzed and we will attempt to identify the pol gene products. HBV will be studied in transfected cultured hapatoblastoma cells to elucidate parameters of virus replication and cell deregulation. HBV/HDV interactions will be compared in Africa and the U.S. in relation to liver cancer and other diseases and the West African HDV, which seems different in replication and disease potential, will be characterized.
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