Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression

Type I interferon (IFN alpha/beta) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFN alpha/beta plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFN alpha/beta in HIV-1 infection is poorly understood. We report significant defects in IFN alpha/beta receptor (IFN alpha/beta R) expression, IFN alpha signaling, and IFN alpha-induced gene expression in monocytes from HIV-1-infected subjects. IFN alpha/beta R expression correlated directly with CD4(+) T-cell count and inversely with HIV-1 RNA level and expression of CD38 by memory (CD45RO(+)) CD8(+) T cells, a measure of pathologic immune activation in HIV-1 infection associated with disease progression. In addition, monocytes from HIV-1-infected persons showed diminished responses to IFN alpha, including decreased induction of phosphorylated STAT1 and the classical interferon-stimulated gene produces MxA and OAS. These IFN alpha responses were decreased regardless of IFN alpha/beta R expression, suggesting that regulation of intracellular signaling may contribute to unresponsiveness to IFN alpha/beta in HIV-1 disease. Defective monocyte responses to IFN alpha/beta may play an important role in the pathogenesis of HIV-1 infection, and decreased IFN alpha/beta R expression may serve as a novel marker of disease progression. (Blood. 2009; 113: 5497-5505)