The Southern California Primary Infection Program includes sites in San Diego and Los Angeles with a track record of identifying substantial cohorts with acute and early HIV infection. These cohorts have participated in longitudinal studies of natural history, pathogenesis, and therapeutic interventions with both antiretroviral drugs and vaccines. A series of excellent collaborations have resulted in completed studies characterizing HIV dynamics, apoptosis, CTL and CD4 proliferate responses, neutralizing antibody, and transmission of HIV drug resistance. These studies consist of both site and AIEDRP-wide studies coordinated in San Diego. Ongoing and proposed studies include the characterization of CD4 and CD8 responses to full length HIV reading frames, the relative contributions of immune responses to consensus and autologous sequences of HIV, the generation of neutralizing antibody (nAb) responses to autologous virus, the emergence of escape mutations over the full length sequence of HIV to each of these immune responses, the role of Nef in CTL control of HIV infection and escape from it, the population biology of HIV in genital secretions, and the dynamics of latent HIV infection in primary infection. We have also coordinated an additional AIEDRP-wide study of CTL responses in preparation for a therapeutic vaccine study. These studies will not only help to better characterize the natural history and pathogenesis of primary HIV infection, they will provide invaluable information to design strategies to prevent HIV transmission, to reduce secondary HIV drug resistance and to design and evaluate strategies for both prophylactic and therapeutic vaccines. A major component of this application is also the commitment to provide a state-of-the-art data management system and methods capable of supporting the projects of multiple local investigators as well as complimenting the resources of the central AIEDRP database. We will develop a set of on-line resources and communications technologies that facilitate scholarly exchange, distance-independent collaboration, information dissemination, education and training.