INHIBITION OF LENTIVIRUS ENVELOPE-MEDIATED CELL FUSION

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Membrane fusion is essential for the infection of target cells by many enveloped viruses, including human immunodeficiency virus (HIV), and is also responsible for syncytium formation after infection. Because of its role in infectivity and pathogenesis, fusion is an attractive target for antiviral therapy. This research project will examine the molecular events involved in lentivirus envelope-mediate cell fusion, and will establish a system for studying specific ways to inhibit fusion, ultimately contributing to the development of a new class of antiviral drugs. Cell fusion mediated by the envelope protein of visna virus, a prototypical lentivirus and close genetic relative of HIV, will be studied because of the broad range of cell types and conditions supporting visna-mediated fusion. The fusion domains of the envelope glycoprotein will be identified by mutational analysis of recombinant envelope expressed by live vaccinia virus vectors. The role of envelop processing in fusion will be studied in fusion-susceptible and fusion-resistant cell lines infected with the vaccinia recombinants. The mechanism of action of polysulfated polysaccharides, which inhibit lentivirus infectivity and envelope mediated cell fusion, will be investigated by examining the interaction between radiolabelled drug and virus, virus envelope protein, and cell surface components. Dr. Flexner is a virologist with research training in recombinant vaccine development and immunology, and clinical training in infectious diseases and clinical pharmacology. The Clinical Investigator Award will be used by the applicant to further develop his skills in molecular virology, and to apply those skills to antiviral drug development. This work will be conducted in the Alan Bernstein Laboratories of the Division of Clinical Pharmacology, a division which is focused largely on the mechanisms of action, toxicity, and clinical use of antimicrobial agents, especially antivirals, and in the Retrovirus Biology Laboratory, multidisciplinary unit studying the molecular biology and pathogenesis of visna, caprine arthritis encephalitis virus, and simian immunodeficiency virus. The applicant intends to transfer information gained in molecular studies of viral pathogenesis to the experimental therapeutics of viral diseases in man, especially AIDS.