HIV and HIV‐Tat inhibit LPS‐induced IL‐27 production in human macrophages by distinct intracellular signaling pathways

HIV inhibition of LPS‐induced IL‐27 production in human macrophages affects cIAP‐1‐TRAF‐6, PI3K, and p38 MAPKs. Monocyte‐derived Mϕs (MDMs) from HIV‐infected patients and MDM infected in vitro with HIV exhibit a reduced ability to secrete various cytokines, including IL‐12. Recently, IL‐27, an IL‐12 family cytokine, was shown to inhibit HIV replication in Mϕ. Whether HIV infection or HIV accessory protein(s) impact IL‐27 production in Mϕs remains unknown. Herein, we show that in vitro HIV infection, as well as intracellular HIV‐Tat (Tat) and Tat peptides, inhibit LPS‐induced IL‐27 production in human MDMs, suggesting impairment of the TLR4 signaling pathway. To understand the signaling pathways governing HIV or Tat‐mediated inhibition of LPS‐induced IL‐27 production, we first demonstrated that p38 MAPK, PI3K, Src‐homology region 2 domain‐containing tyrosine phosphatase 1 (SHP‐1), and Src kinases regulate LPS‐induced IL‐27 production in MDMs. Tat caused down‐regulation of TNFR‐associated factor (TRAF)‐6 and inhibitor of apoptosis 1 (cIAP‐1) and subsequently decreased phosphorylation of downstream PI3K and p38 MAPKs, which were implicated in LPS‐induced IL‐27 production. Whereas SHP‐1 and Src kinases regulated LPS‐induced IL‐27 production, Tat did not inhibit these kinases, suggesting that they were not involved in Tat‐mediated inhibition of LPS‐induced IL‐27 production. In contrast to Tat, in vitro HIV infection of MDM inhibited LPS‐induced IL‐27 production via inhibition of p38 MAPK activation. Overall, HIV and Tat inhibit LPS‐induced IL‐27 production in human macrophages via distinct mechanisms: Tat through the inhibition of cIAP‐1–TRAF‐6 and subsequent inhibition of PI3K and p38 MAPKs, whereas HIV through the inhibition of p38 MAPK activation.