INHIBITION OF LENTIVIRUS ENVELOPE-MEDIATED CELL FUSION

膜融合是许多细胞感染靶细胞所必需的 包膜病毒，包括人类免疫缺陷病毒(HIV)，以及 也负责感染后合胞体的形成。因为它的 在传染性和致病机制中的作用，融合是一个有吸引力的靶点 抗病毒治疗。这项研究项目将考察分子事件 参与慢病毒包膜介导的细胞融合，并将建立一种 用于研究最终抑制核聚变的具体方法的系统 为新型抗病毒药物的开发做出了贡献。细胞 原型性Visna病毒囊膜蛋白的融合 慢病毒和HIV的近亲，将被研究，因为 支持Visna介导的多种细胞类型和条件 核聚变。将确定包膜糖蛋白的融合结构域 用活牛痘表达的重组包膜的突变分析 病毒载体。信封处理在融合中的作用将在 感染该病毒的融合敏感和抗融合细胞系 痘苗重组体。聚硫酸盐的作用机理 抑制慢病毒感染性的多糖和包膜介导 细胞融合，将通过检查相互作用来研究 放射性标记药物和病毒、病毒包膜蛋白和细胞表面 组件。 弗莱克斯纳博士是一名病毒学家，曾接受过重组疫苗研究培训。 传染病的发展和免疫学以及临床培训 和临床药理学。临床研究人员奖将由 申请者进一步发展其在分子病毒学方面的技能，并 将这些技能应用于抗病毒药物的开发。这项工作将是 在临床部艾伦·伯恩斯坦实验室进行 药理学，一个主要专注于 抗菌药物的作用、毒性和临床应用，尤其是 抗病毒药物，以及在逆转录病毒生物学实验室，多学科 绵羊粘虫分子生物学及致病机制研究单位 关节炎脑炎病毒和猴免疫缺陷病毒。这个 申请者打算将在分子研究中获得的信息 病毒致病机制对病毒性疾病实验治疗的影响 男人，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.