title: Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.
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-beta 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-kappaB-dependent manner. SOCS3 expression attenuates the response of macrophages to IFN-beta at proximal levels of pathway activation and downstream antiviral gene expression and consequently overcomes the inhibitory effect of IFN-beta 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-beta 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.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Lisa Nowoslawski
authors.initials: LN
authors.lastname: Akhtar
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Muldowney
authors.forename: Lora L
authors.initials: LL
authors.lastname: Yanagisawa
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D010446:Peptide Fragments; C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D016899:Interferon-beta