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

Interferon a (IFN-a) 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-a during any infection is the macrophage. Thus, macrophages have the potential to produce both IFN-a and HIV In this study, we examined the production of IFN-a and other cytokines by macrophage colony-stimulating factor (M-CSF)treated cultured monorytes during HIV infection . Tumor necrosis factor a (TNF-a), interleukin 1(3 (11,10), IIT6, IFN-w, or IFN-(3 were not detected nor was the mRNA expressed in either uninfected or HIVinfected monorytes. However, both uninfected and HIVinfected monorytes produced high levels of each of these cytokines after treatment with synthetic double-stranded RNA [poly(I)-poly(C)] . Uninfected monorytes also produced high levels ofIFN-a after treatment with poly(I)-poly(C), Newcastle disease virus, or herpes simplex virus . In marked contrast to the preceding observations, HIVinfected monorytes produced little or no IFN-a before or after treatment with any of these agents . The absence of detectable IFN-a activity and mRNA in poly(I).poly(C)-treated HIV-infected monorytes 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-J3 and IFN-w produced by infected cells. The markedly diminished capacity of HIV-infected monorytes to produce IFN-oc may reflect a specific adaptive mechanism ofvirus 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.