Suppressor of cytokine signaling 3 inhibits antiviral IFN-β signaling to enhance HIV-1 replication in macrophages

Lisa Nowoslawski Akhtar, Hongwei Qin, Michelle T. Muldowney, Lora L. Yanagisawa, Olaf Kutsch, Janice E. Clements, Etty N. Benveniste

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

HIV-1 replication within macrophages of the CNS often results in cognitive and motor impairment, which is known as HIV-associated dementia (HAD) in its most severe form. IFN-β suppresses viral replication within these cells during early CNS infection, but the effect is transient. HIV-1 eventually overcomes this protective innate immune response to resume replication through an unknown mechanism, initiating the progression toward HAD. In this article, we show that Suppressor of Cytokine Signaling (SOCS)3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunity within the CNS. We found that SOCS3 is elevated in an in vivo SIV/macaque model of HAD and that the pattern of expression correlates with recurrence of viral replication and onset of CNS disease. In vitro, the HIV-1 regulatory protein transactivator of transcription induces SOCS3 in human and murine macrophages in a NF-κB-dependent manner. SOCS3 expression attenuates the response of macrophages to IFN-β at proximal levels of pathway activation and downstream antiviral gene expression and consequently overcomes the inhibitory effect of IFN-β on HIV-1 replication. These studies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain, such as transactivator of transcription, inhibits antiviral IFN-β signaling to enhance HIV-1 replication in macrophages. This consequence of SOCS3 expression in vitro, supported by a correlation with increased viral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protective innate immune response within the CNS, allowing the recurrence of viral replication and, ultimately, promoting progression toward HAD.

Original languageEnglish (US)
Pages (from-to)2393-2404
Number of pages12
JournalJournal of Immunology
Volume185
Issue number4
DOIs
StatePublished - Aug 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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