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

Type I interferon (IFNα/β) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFNα/β plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFNα/β in HIV-1 infection...

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Veröffentlicht in:Blood 2009-05, Vol.113 (22), p.5497-5505
Hauptverfasser: Hardy, Gareth A.D., Sieg, Scott F., Rodriguez, Benigno, Jiang, Wei, Asaad, Robert, Lederman, Michael M., Harding, Clifford V.
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Sprache:eng
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Zusammenfassung:Type I interferon (IFNα/β) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFNα/β plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFNα/β in HIV-1 infection is poorly understood. We report significant defects in IFNα/β receptor (IFNα/βR) expression, IFNα signaling, and IFNα-induced gene expression in monocytes from HIV-1–infected subjects. IFNα/βR 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 IFNα, including decreased induction of phosphorylated STAT1 and the classical interferon-stimulated gene produces MxA and OAS. These IFNα responses were decreased regardless of IFNα/βR expression, suggesting that regulation of intracellular signaling may contribute to unresponsiveness to IFNα/β in HIV-1 disease. Defective monocyte responses to IFNα/β may play an important role in the pathogenesis of HIV-1 infection, and decreased IFNα/βR expression may serve as a novel marker of disease progression.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-11-190231