HIV PREDOMINANTLY INDUCES IL-1 RECEPTOR ANTAGONIST OVER IL-1 SYNTHESIS IN HUMAN PRIMARY MONOCYTES

Interaction of HIV with cultured human monocytes triggers not only cyt okine production but also the release of natural cytokine inhibitors s uch as the soluble TNF receptors, levels of which are increased in the circulation of HIV-infected patients. We found that HIV-1 LAI induced the production by human monocytes from HIV-seronegative donors of ano ther type of cytokine inhibitor, the IL-1 receptor antagonist (IL-1Ra) . HIV mainly induced the secreted form (83%) of IL-1Ra through de novo mRNA synthesis. IL-1Ra production was triggered at an early step of t he infection process and involved the HIV envelope protein and the CD4 receptor. HIV-triggered IL-1Ra production occurred after a lag time, suggesting an indirect mechanism. Neutralizing Abs to IL-1 beta and IL -10 had no effect, while simultaneous treatment with anti-TNF-alpha, a nti-granulocyte-macrophage CSF, and anti-TGF-beta nearly abrogated IL- 1Ra release, supporting an indirect induction through the concerted ac tion of the co-produced cytokines. IL-1Ra was induced by HIV in a mean 1,000-fold increase over IL-1 alpha beta, a ratio 20-fold higher than that obtained with LPS. This production masked 80% of IL-1 bioactivit y in HIV-induced monocyte supernatants. These results suggest that the net balance between pro-inflammatory cytokines and their natural inhi bitors could be critical in the control of the inflammatory process as sociated with HIV infection.