Aim 1A: Identify virologic targets of cellular immune response and purifying selection during the establishment of HIV-1 infection with the goal of comprehensively identifying sites within the virus of differential selection during the establishment of HIV-1 infection. These studies will guide generation of peptides for studies of autologous virus immune recognition (Project 2) and the impact of these structural changes on function (Project 3). We will test the following hypotheses: a) There are multiple sites encoded on the viral genome that are subject to strong selective pressures early in infection. b) A major subset of these sites are important in determining cellular immunological escape. c) Aim 1B: Track the spread and persistence of HIV-1 within T cells, monocytes and macrophages during the establishment of infection in new host. We will test these hypotheses: d) Early HAART will suppress HIV-1 replication significantly in CD4 + T cells but less so in blood monocytes and tissue macrophages. This will bias the origin of continuing viral replication to monocyte/macrophages. e) Monocytes/macrophages are major sources of HIV-1 that are transmitted or that establish new infection in patients. f) Monocyte/macrophages are the proximal sources of virus variants found in plasma following interruption or cessation of therapy. g) Early antiretroviral therapy influences the cellular origin of virus seeding later infection. h) Measurement of virus reservoirs and antiviral drug resistance markers will provide sensitive indicators of ongoing replication during suppressive HAART. i) Transmitted or selected populations of drug-resistant virus in monocytes/macrophages serve as a reservoir of drug-resistant virus. j) When drug-resistant virus is detectable within PBMC using a highly sensitive oligoligase assay (OLA), a drug-resistant population will eventually overcome the suppressive activity of HAART.