Active cellular infection of myeloid cells is required for HIV-1-mediated suppression of interleukin-12 p40 expression.

Immunodeficiency during HIV infection is associated with impaired production of interleukin-12 (IL-12). Here we examine the requirement for active cellular infection, the role of other cytokines, and the molecular target of HIV-mediated suppression of IL-12. The reduction in LPS-induced IL-12 p40 protein and mRNA following acute in vitro HIV infection of THP-1 cells and monocytes was not attributed to IL-10 or TGF-beta activity and was not restored by priming with IL-4, IL-13, or IFN-gamma. Suppression of IL-12 was dependent upon active cellular infection and replication and not due to any soluble host or viral factors in HIV-infected cultures. Significant reduction in transcription of IL-12 p40 was observed following acute HIV infection. These results suggest that impaired IL-12 production in HIV-infected myeloid cells occurs, in part, via disruption of IL-12 p40 gene expression in a manner that requires cellular infection, highlighting the need to study myeloid cells in isolation during acute HIV-1 infection.

Normalization of natural killer cell function and phenotype with effective anti-HIV therapy and the role of IL-10.

OBJECTIVES: Natural killer (NK) cell function is likely to be important in controlling HIV infection and opportunistic pathogens. We therefore evaluated NK function and phenotype over the course of antiretroviral therapy (ART) and examined the potential mechanisms of altered NK activity in HIV infection. METHODS: We measured NK cell percentage, NK cytolytic activity (both by flow cytometry) and plasma IL-10 concentrations (by enzyme-linked immunosorbent assay) in 10 HIV-seropositive patients before and over one year of effective ART. To examine potential mechanisms of altered NK activity, we measured NK receptor expression in ART treated and untreated HIV-positive individuals by flow cytometry. As IL-10 enhances NK activity, we studied the effect of IL-10 on NK receptor expression and activity in peripheral blood mononuclear cells (PBMC) from HIV-seronegative individuals. RESULTS: NK cytolytic activity was elevated in HIV infection and decreased with ART to levels observed in HIV-negative individuals. A greater proportion of NK cells from untreated HIV-positive individuals expressed the NK receptors CD158a and CD161 than either HIV-negative volunteers or effectively treated HIV-positive patients. NK cells from PBMC incubated with IL-10 demonstrated increases in CD158a, CD161 and CD94 expression and increases in cytolytic activity. The treatment-associated decrease in NK activity paralleled a decrease in IL-10 production. CONCLUSION: The observation that IL-10 alters NK receptor expression similar to that observed in HIV infection, and the fact that NK receptor expression and activity normalize in parallel with ART-induced reduction of circulating IL-10 levels supports a role for IL-10 in NK cell activity and HIV immunopathogenesis.