A selective defect of interferon α production in human immunodeficiency virus-infected monocytes

Abstract

Interferon α (IFN-α) induces significant antiretroviral activities that affect the ability of human immunodeficiency virus (HIV) to infect and replicate in its principal target cells, CD4+ T cells and macrophages. A major endogenous source of IFN-α during any infection is the macrophage. Thus, macrophages have the potential to produce both IFN-α and HIV. In this study, we examined the production of IFN-α and other cytokines by macrophage colony-stimulating factor (M-CSF)-treated cultured monocytes during HIV infection. Tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IFN-ω, or IFN-β were not detected nor was the mRNA expressed in either uninfected or HIV-infected monocytes. However, both uninfected and HIV-infected monocytes produced high levels of each of these cytokines after treatment with synthetic double-stranded RNA [poly(I)·poly(C)]. Uninfected monocytes also produced high levels of IFN-α after treatment with poly(I)·poly(C), Newcastle disease virus, or herpes simplex virus. In marked contrast to the preceding observations, HIV-infected monocytes produced little or no IFN-α before or after treatment with any of these agents. The absence of detectable IFN-α activity and mRNA in poly(I)·poly(C)-treated HIV-infected monocytes was coincident with high levels of 2′,5′ oligoadenylate synthetase and complete ablation of HIV gene expression. The antiviral activity induced by poly(I)·poly(C) may be a direct effect of this synthetic doubled-stranded RNA or secondary to the low levels of IFN-β and IFN-ω produced by infected cells. The markedly diminished capacity of HIV-infected monocytes to produce IFN-α may reflect a specific adaptive mechanism of virus to alter basic microbicidal functions of this cell. The inevitable result of this HIV-induced cytokine dysregulation is virus replication and persistence in mononuclear phagocytes.