ABSTRACT
Despite viral suppression by effective combined antiretroviral therapy, HIV-1-infected individuals have an increased risk of non-AIDS-related overall morbidity, which is due to the persistent chronic inflammation exemplified by the activation of monocytes, such as increased CD16high subset, and elevated plasma level of soluble CD163 (sCD163) and soluble CD14 (sCD14). Here, we show that IL-10, which has been recognized as anti-inflammatory, induces these activated phenotypes of monocytes in vitro. IL-10 increased CD16high monocytes, which was due to the upregulation of CD16 mRNA expression and completely canceled by an inhibitor of Stat3. Moreover, IL-10 increased the production of sCD163 and sCD14 by monocytes, which was consistent with the upregulation of cell surface expression of CD163 and CD14, and mRNA expression of CD163. However, unlike the IL-10-indeuced upregulation of CD16, that of CD14 was minimally affected by the Stat3 inhibitor. Furthermore, the IL-10-induced upregulation of CD163 protein and mRNA was partially inhibited by the Stat3 inhibitor, but completely canceled by an inhibitor of AMPK, an upstream kinase of Stat3 and PI3K/Akt/mTORC1 pathways. In this study, we also found that HIV-1 pathogenic protein Nef, which is known to persist in plasma of virally-suppressed individuals, induced IL-10 production in monocyte-derived macrophages. Our results may suggest that IL-10, which is inducible by Nef-activated macrophages, is one of drivers for activated phenotypes of monocytes in virally-suppressed individuals, and that IL-10 induces the increased CD16high monocytes and elevated level of sCD163 and sCD14 through the activation of different signaling pathways.
ABSTRACT
The proinflammatory cytokine IL-32 is elevated in the plasma and tissues of HIV-1-infected individuals. However, its significance in HIV-1 infection remains unclear because IL-32 inhibits and stimulates viral production in monocyte-derived macrophages (MDMs) and CD4+ T cells, respectively. In this study, we initially found that the inhibitory effect on human MDMs depends on SAMHD1, a dNTP triphosphohydrolase that inhibits viral reverse transcription. IL-32 increased the unphosphorylated active form of SAMHD1, which was consistent with the reduced expression of the upstream cyclin-dependent kinases. Indeed, IL-32 lost its anti-HIV-1 activity in MDMs when SAMHD1 was depleted. These results explain why IL-32 inhibits HIV-1 in MDMs but not CD4+ T cells, because SAMHD1 restricts HIV-1 in noncycling MDMs but not in cycling CD4+ T cells. Another unique feature of IL-32 is the induction of the immunosuppressive molecule IDO1, which is beneficial for HIV-1 infection. In this study, we found that IL-32 also upregulates other immunosuppressive molecules, including PD-L1, in MDMs. Moreover, IL-32 promoted the motility of MDMs, which potentially facilitates intercellular HIV-1 transmission. Our findings indicate that IL-32 has both the direct inhibitory effect on HIV-1 production in MDMs and the indirect stimulatory effects through phenotypic modulation of MDMs, and they suggest that the stimulatory effects may outweigh the inhibitory effect because the window for IL-32 to inhibit HIV-1 is relatively confined to SAMHD1-mediated reverse transcription suppression in the viral life cycle.
