This Clinical Investigator Award proposal outlines a three-year plan aimed at providing intensive training in the field of HIV-1 molecular biology to prepare the candidate for a career as an independent scientific investigator in AIDS research. The laboratory research will be supervised by Dr. Joseph Sodroski and Dr. William Haseltine at the Dana-Farber Cancer Institute. The focus of the research will be on the function of the HIV-1 envelope glycoprotein carboxyl terminus. 'Me HIV-1 envelope carboxyl terminus contains sequences which are essential for efficient viral replication but the function of this domain is currently unknown. An HIV-1 envelope expressor plasmid will be used to identify and characterize replication-defective carboxyl terminus mutants in transfected COS-1 and Jurkat T cells, A variety of biological and -biochemical assays will be used to analyze the synthesis, processing, stability, multimerization, incorporation into virions, cell surface expression, CD4 binding, and membrane-fusing ability of selected HIV-1 envelope carboxyl terminus mutants. We anticipate that understanding the structure and function of this unique domain will elucidate some of the fundamental mechanisms which are involved in HIV-1 replication and cytopathicity. Furthermore, the development of theoretical structural models for the HIV-1 envelope glycoproteins is likely to provide hypotheses which will help to guide future experimental work and be of value for drug and vaccine design.
