INHIBITION OF LENTIVIRUS ENVELOPE-MEDIATED CELL FUSION

膜融合对于许多细胞感染靶细胞是必不可少的。 包膜病毒，包括人类免疫缺陷病毒（HIV）， 也负责感染后合胞体的形成。由于其 在感染性和发病机制中的作用，融合是一个有吸引力的目标， 抗病毒治疗这个研究项目将检查分子事件 参与慢病毒介导的细胞融合，并将建立一个 一个研究抑制核聚变的具体方法的系统， 有助于开发一类新的抗病毒药物。细胞 由维斯纳病毒的包膜蛋白介导的融合， 慢病毒和艾滋病毒的近亲，将进行研究，因为 广泛的细胞类型和条件支持visna介导的 核聚变将鉴定包膜糖蛋白的融合结构域 通过活牛痘表达的重组包膜的突变分析， 病毒载体在融合中包络处理的作用将在 融合敏感和融合抗性细胞系感染 牛痘重组体。多硫酸酯的作用机理 多糖，其抑制慢病毒感染性和包膜介导的 细胞融合，将通过检查之间的相互作用， 放射性标记的药物和病毒、病毒包膜蛋白和细胞表面 件. 博士Flexner是一名接受过重组疫苗研究培训的病毒学家 发展和免疫学以及传染病临床培训 和临床药理学。临床研究者奖将用于 申请人进一步发展其在分子病毒学方面的技能， 将这些技能应用于抗病毒药物的开发。这项工作将 在临床部的Alan伯恩斯坦实验室进行 药理学，一个主要集中在药物作用机制上的部门， 抗菌药物的作用、毒性和临床应用，特别是 在逆转录病毒生物学实验室，多学科 研究山羊visna的分子生物学和发病机理的单位 关节炎脑炎病毒和猿猴免疫缺陷病毒。的 申请人打算转移在分子研究中获得的信息， 病毒致病机理与病毒性疾病的实验治疗 尤其是艾滋病。

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.