HIV GP120/GP41 ANALYSIS USING MONOCLONAL ANTIBODIES

这项提议所依据的基本假设是 对猪瘟病毒包膜蛋白表位结构的认识 HIV病毒和人类淋巴细胞T4受体将使我们能够 了解这些蛋白质上的功能位点 它们参与了GP 120-T4受体的相互作用。是这样的 知识将导致能够预防初始 在已确定的感染中感染和传播病毒。为了测试这一点 假设我们提出了以下三个具体目标。1)我们 关于表征HIV包膜表位结构的建议 蛋白质和人类T4受体通过在一个 功能和结构水平的一系列小鼠单抗 针对包膜蛋白和人类T4受体的抗体。 2)我们建议开发人-鼠嵌合抗体 以选定的“功能性”gp120表位为靶标。一次搜查将 这类抗体优先结合于 HIV免疫系统通常不识别的表位 被感染的人。将对这些嵌合抗体进行检测 它们与表达HIV包膜蛋白的细胞结合的能力， 在与表面结合后被内吞，并介导 外源蛋白存在下表达包膜蛋白细胞的细胞溶解 人类补充物。3)。我们建议开发一系列反 抗鼠独特型抗体的单抗 识别“功能上”重要的gp 120表位 识别人T4抗原表位的单抗 淋巴细胞受体。这些抗独特型抗体将是 通过序列分析和分子模拟研究确定 他们的独生子的三维结构。以这种方式， 我们计划在上定义功能表位的立体结构 包膜蛋白和T4受体。除了……之外 发展这些具体目标，这项提案将作为核心 一种用于生产单抗的单抗设备 本国家计划1、2、3、4、5、AD7中的研究试剂 艾滋病药物研发合作小组。

The principle hypothesis upon which this proposal is based is that knowledge of the epitope structure of the envelope protein of the HIV virus and the human lymphocyte T4 receptor will allow us to develop an understanding of the functional sites on these proteins which are involved in gp 120-T4 receptor interaction. Such knowledge will lead to modalities capable of preventing initial infection and spread of virus in established infection. To test this hypothesis we propose the following three specific aims. 1) We propose to characterize the epitope structure of the HIV envelope protein and the human T4 receptor by developing and defining at a functional and structural level a series of murine monoclonal antibodies to the envelope protein and to the human T4 receptor. 2) We propose to develop human-murine chimeric antibodies targeted for selected "functional" gp120 epitopes. A search would be made for such antibodies which would preferentially bind to epitopes not normally recognized by the immune system of HIV infected individuals. These chimeric antibodies will be tested for their ability to bind to cells expressing the HIV envelope protein, to be endocytosed after binding to the surface, and to mediate cytolysis of cells expressing envelope protein in the presence of human complement. 3). We propose to develop a series of anti- idiotype antibodies to murine monoclonal antibodies which recognize "functionally" important gp 120 epitopes and to monoclonal antibodies whose epitopes recognize the human T4 lymphocyte receptor. These anti-idiotypes antibodies will be studied by sequence analysis and molecular modeling to determine the three dimensional structure of their idiotopes. In this manner, we plan to define the steric structure of functional epitopes on the envelope protein and the T4 receptor. In addition to developing these specific aims, this proposal will serve as a core monoclonal antibody facility for the production of monoclonal reagents for studies in programs 1, 2, 3, 4, 5, ad 7 of this National Cooperative Drug Discovery Group for AIDS.