The long-term objective of this research is to understand how physiologic events of immune system activation in vivo contribute to the pathogenesis of AIDS. This proposal is based on observations made using the simian immunodeficiency virus (SIV) model, a primate lentivirus homologous to HIV which causes a lethal immunodeficiency in macaques that is clinically indistinguishable from AIDS in humans. In preliminary work we found that a subset of CD4+ lymphocytes expressing high levels of the adhesion molecule CD44 was selectively depleted at an asymptomatic phase of SIV infection. This T cell phenotype is acquired during post-thymic differentiation and indicates that maturational events are required for permissiveness to SIV in vivo. Using a polymerase chain reaction (PCR) technique, we have directly determined that within this susceptible subset, both activated cells and non-cycling memory cells are infected in vivo. We hypothesize that memory cells are a reservoir for latent infection in vivo, and that reactivation by antigen stimulates viral replication, leading to cell destruction and ablation of the memory response. The goals of this study are: 1) To ascertain the nature of SIV gene expression in activated and resting, memory T cell subsets in vivo, using a PCR assay which we have shown can sensitively detect mRNA for gag, env, tat, nef, vif, vpr, and vpx genes. 2) To determine which viral genes may be involved in the reactivation of latent SIV infection in memory cells stimulated by recall antigen; 3) To study the effects of recall immunization on a) SIV activity and specific gene expression in vivo in infected macaques, and b) memory cell deletion or dysfunction. The candidate, Dr. Dennis Willerford, is a physician with 5 years postdoctoral experience in clinical medicine and basic research. For 2 1/2 years he has been in the laboratory of Dr. W. M. Gallatin at the Fred Hutchinson Cancer Research Center. His work has included studies of lymphocyte migration, expression of adhesion receptors for high endothelium, and T cell activation, prior to the work described here. The combined facilities of the Hutchinson Center and the Department of Microbiology and the Regional Primate Research Center at the University of Washington provide a rich, interactive environment for solid training in molecular and cellular biology, as well as the specific resources necessary for this project. This period of this grant will allow the candidate to develop both his research skills and his project to a level appropriate for an independent, faculty-level investigator.