A multi-institutional group seeks to renew funding to support the continuation of its cooperative effort to develop novel classes of drugs which inhibit HIV-1 replication. This proposal consists of 5 projects that represent an integrated program using a rational approach to develop anti-HIV-1 drugs. Three of the projects based at academic institutions will apply fundamental knowledge to the development of biochemical and cell based assays for key components of HIV-1. Specific targets include the HIV-1 integrase, vpr protein, capsid packaging functions and ribonucleaseH. Work on reverse transcriptase and gp120-CD4 interactions will continue as well as work on selected new areas in the design of protease inhibitors. The fourth project based at an academic institution will address problems of resistance of HIV-1 to anti-viral therapy. To this end, fundamental studies of drug resistance will be carried out. Strains of SIV resistant to anti-viral drugs will be made, and an animal model, SIVMac, will be used to develop means of overcoming clinical resistance. The industrial partner is well equipped to apply the latest methods of drug development to HIV-1 therapy and is experienced in bringing drugs from the development state to clinical trials. The group includes three laboratories from the Dana-Farber Cancer Institute, one laboratory from Columbia University, and scientists at SmithKline Beecham Pharmaceuticals. The group also includes sub-projects to be carried out at the Delta Regional Primate Research Center and at the Albert Einstein College of Medicine. Together these institutions provide a pool of research unattainable at any single institution. The experience and proven ability of this group to work together productively insures that this program will continue to be successful.