Nitric oxide production in HIV-1 infected patients receiving intermittent cycles of interleukin-2 and antiretrovirals

Background: Interleukin-2 (IL-2) has been investigated as an adjunct to antiretroviral therapy (ART) because of its well-demonstrated capacity of stably increasing the number of peripheral CD4+ T cell lymphocytes. However, IL-2-related adverse events (AEs), including fever, tachycardia, hypotension, and respiratory failure, are typically close- and schedule-dependent and can potentially limit the application of IL-2 therapy in an outpatient setting. Nitric oxide (NO) is a potent vasodilator potentially responsible for some of the AEs caused by IL-2. Purpose: In this study, we determined NO production in a cohort of HIV-1 infected individuals receiving ART either alone or together with IL-2. Method: NO production, detected as plasma nitrate/nitrite levels by the Griess reaction, was evaluated in 3 groups of 10 individuals each. In the first group, subcutaneous (sc) administration of 12-15 million international units per day (MIU/d) of IL-2 was administered for 5 days every 8 weeks for 6 cycles together with ART; in the second group, IL-2 (6 MIU/d) was given sc for 5 days every 4 weeks for 12 cycles together with ART; whereas the third group received ART alone. Results: At baseline, the plasma nitrate/nitrite levels in the 2 groups of patients who received high and low doses of the cytokine along with ART were 28.5 +/- 18.1 mumol/L and 34.2 +/- 29.0 mumol/L, respectively. These levels were comparable to those of patients treated with only ART (18.6 +/- 22.4 mumol/L) and to those of 20 healthy controls (19.9 +/- 5.9 mumol/L). No significant increase of plasma nitrate/nitrite levels was observed by administration of either ART or ARTAL-2. In addition, NO production was not associated significantly with different levels of tumor necrosis factor-alpha, IL-6, or soluble IL-2 receptor alpha chain in 9 individuals with WHO grade 2 and 3 AEs. Conclusion: Our results indicate that NO is unlikely to be responsible for most side effects of IL-2 therapy in HIV-1 infected individuals. Because both IL-2 and virus multiplication have been reported to independently stimulate NO production, concomitant ART may curtail NO production through inhibition of HIV-1 replication.