An intensive effort was directed toward examining the relationships between changes in viral burden, changes in viral genotype and phenotype, and changes in immunologic function in patients with human immunodeficiency virus (HIV) infection receiving a variety of anti-retroviral agents with different mechanisms of action either alone or in combination. The increases in CD4+ T lymphocytes observed following anti-retroviral therapy were found to be due to increases in the existing peripheral pool of T cells rather than through stem cell differentiation via a thymic environment. Specific immune responses could be generated to neoantigens such as keyhole limpet hemocyanin following repeated immunizations as long as the immunizations occurred prior to a significant decline in the overall T lymphocyte count. A study was competed comparing combination reverse transcriptase inhibitor therapy to monotherapy utilizing the nucleoside analogues zidovudine and didanosine and the non-nucleoside delavirdine. The best responses in terms of increases in CD4+ T lymphocyte counts and decreases in levels of HIV RNA were seen in patients receiving the 3-drug combination. The response to combination anti-retroviral therapy using 3 reverse transcriptase inhibitors in combination was worse in those patients with a pre-existing zidovudine-resistance mutation at the 215 codon. The patterns of viral resistance that emerged in vivo were quite distinct from those generated in vitro. The branched-DNA (bDNA) technique was found capable of quantitatively measuring changes in viral burden in large numbers of samples to a significantly greater degree than existing techniques. The rate of CD4+ T-cell count decline in a cohort of patients managed with combination anti-retroviral therapy was determined to be related to baseline levels of HIV RNA. Work was initiated on a phase I clinical trail of a novel antiretroviral agent working through inhibition of the zinc-finger domain of the p7 protein of HIV-1.