Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression.
Type I interferon (IFNalpha/beta) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFNalpha/beta plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFNalpha/beta in HIV-1 infection is poorly understood. We report significant defects in IFNalpha/beta receptor (IFNalpha/betaR) expression, IFNalpha signaling, and IFNalpha-induced gene expression in monocytes from HIV-1-infected subjects. IFNalpha/betaR 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 IFNalpha, including decreased induction of phosphorylated STAT1 and the classical interferon-stimulated gene produces MxA and OAS. These IFNalpha responses were decreased regardless of IFNalpha/betaR expression, suggesting that regulation of intracellular signaling may contribute to unresponsiveness to IFNalpha/beta in HIV-1 disease. Defective monocyte responses to IFNalpha/beta may play an important role in the pathogenesis of HIV-1 infection, and decreased IFNalpha/betaR expression may serve as a novel marker of disease progression.
Hardy
Gareth A D
GA
Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106-7288, USA.
Sieg
Scott F
SF
Rodriguez
Benigno
B
Jiang
Wei
W
Asaad
Robert
R
Lederman
Michael M
MM
Harding
Clifford V
CV
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D024882:Drug Resistance, Viral / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007110:Immunity, Active / Q000187:drug effects; D007370:Interferon Type I / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D017471:Receptors, Interferon / Q000378:metabolism
D000998:Antiviral Agents; D015415:Biomarkers; D007370:Interferon Type I; D017471:Receptors, Interferon