INTERLEUKIN-10 ENHANCES HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 EXPRESSION IN A CHRONICALLY INFECTED PROMONOCYTIC CELL-LINE (U1) BY A TUMOR-NECROSIS-FACTOR ALPHA-INDEPENDENT MECHANISM

TNF-alpha enhances HIV-1 replication in acutely and chronically infect ed cells and likely contributes to the wasting associated with the acq uired immunodeficiency syndrome. Agents that inhibit TNF-alpha activit y should theoretically delay the progression of disease, and several a re currently in clinical trials. We hypothesized that IL-10, a cytokin e that suppresses the gene expression and synthesis of TNF-alpha in mo nocytic cells, might inhibit HIV-1 replication. As expected, IL-10 sup pressed PMA-induced TNF-alpha production in U1 cells; however, when U1 cells were cultured in the presence of PMA and increasing doses of IL -10, a dose-dependent increase in HIV-1 expression was observed. IL-10 also enhanced IL-1 beta-, TNF-alpha-, and GM-CSF-induced HIV-1 expres sion in U1 cells, and this occurred, at least in part, at the level of transcription. We next stimulated cells under conditions of TNF-alpha blockade. When PMA-induced TNF-alpha activity and HIV-1 replication w ere blocked by the presence of soluble TNF receptors, IL-10 independen tly enhanced HIV-1 replication. In contrast, other agents that are cap able of blocking TNF-alpha synthesis or TNF-alpha activity either had no effect (IL-13 and IL-4) or inhibited HIV-1 expression (soluble TNF receptors and pentoxifylline) in UI cells. These data suggest that IL- 10, while inhibiting TNF-alpha synthesis, has an independent mechanism of action that enhances HIV-1 replication. Therefore, IL-10 may have undesirable effects in HIV-1-infected patients.