| Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. | |
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MedLine Citation:
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PMID: 20631305 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Lisa Nowoslawski Akhtar; Hongwei Qin; Michelle T Muldowney; Lora L Yanagisawa; Olaf Kutsch; Janice E Clements; Etty N Benveniste |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-07-14 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-05 Completed Date: 2010-09-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 2393-404 Citation Subset: AIM; IM |
Affiliation:
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Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AIDS Dementia Complex
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immunology,
virology Animals Antiviral Agents / pharmacology Cell Line Cells, Cultured Gene Expression / drug effects HIV Infections / immunology, virology HIV-1 / immunology* Humans Interferon-beta / pharmacology* Macaca mulatta Macrophages / immunology*, metabolism, virology Mice Mice, Inbred C57BL Peptide Fragments / pharmacology Phosphorylation / drug effects Reverse Transcriptase Polymerase Chain Reaction STAT Transcription Factors / metabolism Signal Transduction / drug effects, immunology Simian Acquired Immunodeficiency Syndrome / immunology, virology Simian immunodeficiency virus / immunology Suppressor of Cytokine Signaling Proteins / genetics, immunology*, metabolism Virus Replication / drug effects, immunology tat Gene Products, Human Immunodeficiency Virus / chemistry, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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AI064012/AI/NIAID NIH HHS; AI077457/AI/NIAID NIH HHS; F30-NS-65600/NS/NINDS NIH HHS; MH70306/MH/NIMH NIH HHS; NS050028/NS/NINDS NIH HHS; NS055648/NS/NINDS NIH HHS; NS45290/NS/NINDS NIH HHS; NS47984/NS/NINDS NIH HHS; NS50665/NS/NINDS NIH HHS; NS57563/NS/NINDS NIH HHS; T32-AI-07493/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antiviral Agents; 0/Peptide Fragments; 0/SOCS3 protein, human; 0/STAT Transcription Factors; 0/Socs3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/tat Gene Products, Human Immunodeficiency Virus; 77238-31-4/Interferon-beta |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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