Interleukin-2 is a cytokine with important regulatory properties for both T and B cells. The current studies were undertaken to evaluate the toxicity and obtain preliminary evidence of the efficacy of the combination of antiretroviral therapies and interleukin-2 in the treatment of HIV infection. Our studies initially focused on patients with CD4 counts above 200 cells/mm3, and used dose escalations to determine maximum tolerated doses. In the next phase of the study, ten patients with CD4 counts above 200 cells/mm3 received IL-2 beginning at a dose of 18 million units per day by continuous infusion for 5 days every 2 months for a period of over one year. The courses of IL-2 were well-tolerated, although most of the patients required dosage reductions due to IL-2 related adverse effects. Sustained improved in CD4 number have been seen in six of these 10 patients. This was associated with an increase in the proportion of cells (primarily CD4 positive cells) that are IL-2 receptor positive, and a decrease in the proportion of primarily CD8 cells that are HLA- DR positive. There also appears to be a transient increase in viral load as measured by the bDNA assay seen at day 6-day 8 following initiation of IL-2 therapy. The study was subsequently expanded to evaluate patients with CD4 counts under 200 cells/mm3. Among 15 patients who enrolled in this group, no responses were seen in the patients with CD4 counts under 100 cells/mm3, although sustained evidence of viral activation as measured by both bDNA and p24 assays was detected. In the patients with CD4 counts between 100-200 cells/mm3, a minority have shown an improvement. Again, evidence of viral activation that appeared to be more sustained was seen. To try to improve the antiretroviral regimen, some patients received delavirdine (a non-nucleoside RT inhibitor), but with no obvious benefit to date. Based on the preliminary results seen in this open trial, we have undertaken a randomized trial to evaluate IL-2 therapy in patients with CD4 counts above 200 cells/mm3 in combination with currently approved antiretroviral therapies. The study opened in April 1993 and completed enrollment by December 1993, with 60 patients enrolling. The study is planned to continue for a 14-month follow-up period. These studies are potentially important because they are the first ones to suggest that immunomodulating agents combined with antiretroviral agents may have a benefit in patients with HIV Infection. To date, this benefit has been restricted to patients with CD4 counts above 100 cells/mm3.