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

Abstract

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.

• Authors: Gareth A D Hardy, Scott F Sieg, Benigno Rodriguez, Wei Jiang, Robert Asaad, Michael M Lederman, Clifford V Harding
• Journal: Blood (Blood) Vol. 113 Issue 22 Pg. 5497-505 (May 28 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19299650 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiviral Agents
• Biomarkers
• Interferon Type I
• Receptors, Interferon

Topics

• Adult
• Antiviral Agents (therapeutic use)
• Biomarkers (blood)
• Case-Control Studies
• Cross-Sectional Studies
• Disease Progression
• Drug Resistance, Viral (immunology)
• Female
• HIV Infections (blood, drug therapy, immunology)
• HIV-1 (immunology)
• Humans
• Immunity, Active (drug effects)
• Interferon Type I (therapeutic use)
• Male
• Middle Aged
• Monocytes (metabolism, pathology)
• Receptors, Interferon (metabolism)