Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.
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.
Akhtar
Lisa Nowoslawski
LN
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Qin
Hongwei
H
Muldowney
Michelle T
MT
Yanagisawa
Lora L
LL
Kutsch
Olaf
O
Clements
Janice E
JE
Benveniste
Etty N
EN
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
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