Efforts were directed toward attempting to better understand the underlying immunopathologic mechanisms of HIV infection through a detailed analysis of T-cell subset characteristics in patients both before and after highly active antiretroviral therapy as well as through the use of the Hu-PBL-SCID animal model of HIV infection. A preferential decline in naive CD4+ T cells was noted in HIV-infected individuals as the total CD4+ T-cell count declined. Following therapy, numbers of naive CD4+ T cells increased only if they were present prior to the initiation of therapy. Disruptions of the CD4+ T cell receptor (TCR) repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Anti-viral or IL-2 therapy-induced changes in CD4+ T-cell counts, while often substantial in number, led to only minor changes in previously disrupted repertoires. The CD8+DR+ lymphocytes isolated from the peripheral blood of HIV patients differed from control CD8+DR+ cells obtained from uninfected individuals and activated through the TCR, in that they lacked expression of CD25 and CD69 and were not actively involved in cell cycle progression. Moreover, these cells did not proliferate to various mitogens and showed a high rate of programmed cell death when cultured in vitro. Despite their increased cell death rate and inability to divide, CD8+DR+ cells from patients with HIV produced substantial levels of the beta-chemokines MIP-1alpha and RANTES. Levels of cdk2 and cyclin E were elevated in CD8+DR+ cells, while levels of p16ink4 were decreased suggesting that these CD8+DR+ cells had arrested in the G1 phase of the cell cycle. The TCR Vbeta repertoire of CD8 cells from patients infected with HIV was highly skewed, with the majority of TCR Vbeta expansions occurring within the DR+ fraction. Twenty-one genes found to be differentially expressed between the DR+ and DR- CD8+ subsets are currently being characterized. The Hu-PBL-SCID model was modified to enable better simulation of natural infection by transferring critical elements of the human immune system together with host-adapted virus. In contrast to animals reconstituted with cells from patients with AIDS, mice reconstituted with cells from long-term nonprogressors or slow progressors did not demonstrate CD4+ T-cell depletion. Further, mice reconstituted with cells from long-term non-progressors resisted challenge with a second source of virus. Treatment with the novel nucleoside analogue FddA significantly reduced CD4+ T-cell depletion and inhibited viral recovery.