IL-10 COOPERATES WITH TNF-ALPHA TO ACTIVATE HIV-1 FROM LATENTLY AND ACUTELY INFECTED-CELLS OF MONOCYTE MACROPHAGE LINEAGE/

IL-10 is elevated in HIV-1-infected individuals and has been implicate d in disease progression, In this study, we investigated the effects o f IL-10 on the activation of HIV-1 from infected monocytes and macroph ages, Although IL-10 alone did not induce HIV-1 replication, in the pr esence of TNF-alpha, IL-10 markedly enhanced virion production from a chronically infected promonocytic cell line (U1) and in acutely infect ed monocyte-derived macrophages, Neutralizing mAbs to IL-10 and TNF-al pha indicated that both cytokines were essential for the induction and were required to generate a synergistic increase in virus expression, The effects of the two cytokines were distinguishable functionally si nce pretreatment with TNF-alpha attenuated the cytokine cooperativity, while pretreatment with IL-10 potentiated their cooperativity, sugges ting that IL-10 and TNF-alpha play different roles in the activation o f virus, Northern blot analysis as well as Ab blocking and cytokine se cretion studies indicated that the induction of either endogenous TNF- alpha or IL-10 was not involved in the cooperativity, nor was an up-re gulation of TNF-alpha receptors, In combination with TNF-alpha, IL-10 stimulated activating protein-1 (AP-1) and nuclear factor (NF)-kappa B binding activities and cooperated to increase HIV-1 steady-state mRNA levels and enhance long terminal repeat-directed transcription throug h activation of the NF-KB binding sites, suggesting the IL-10 effect o ccurs at least in part at the transcriptional level, These results ind icate that IL-10, in addition to down-regulating the cellular immune r esponse to HIV-1, may also play a role in TNF-alpha-mediated activatio n of HIV-1 replication in the monocyte/macrophage lineage.