HIV GP120/GP41 ANALYSIS USING MONOCLONAL ANTIBODIES

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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.