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 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 completed 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. A phase I clinical trial of a novel antiretroviral agent that exerts its effects through inhibition of the zinc-finger domain of the p7 protein of HIV-1 was initiated. A study was begun to identify persistent reservoirs of HIV infection in persons receiving long-term combination therapy with antiretroviral agents including a protease inhibitor (indinavir), a non-nucleoside reverse transcriptase inhibitor (nevirapine), and 2 nucleoside reverse transcriptase inhibitiors (zidovudine and lamivudine). A clinical trial was initiated to determine whether elevated CD4+ T-lymphocyte counts resulting from antiretroviral therapy are effective in controlling the progression of cytomegalovirus retinitis in persons with HIV infection.
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