| RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I. | |
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MedLine Citation:
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PMID: 21084468 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The rapid induction of type I interferon (IFN) is essential for establishing innate antiviral responses. During infection, cytoplasmic viral RNA is sensed by two DExD/H box RNA helicases, RIG-I and MDA5, ultimately driving IFN production. Here, we demonstrate that purified genomic RNA from HIV-1 induces a RIG-I-dependent type I IFN response. Both the dimeric and monomeric forms of HIV-1 were sensed by RIG-I, but not MDA5, with monomeric RNA, usually found in defective HIV-1 particles, acting as a better inducer of IFN than dimeric RNA. However, despite the presence of HIV-1 RNA in the de novo infection of monocyte-derived macrophages, HIV-1 replication did not lead to a substantial induction of IFN signaling. We demonstrate the existence of an evasion mechanism based on the inhibition of the RIG-I sensor through the action of the HIV-1 protease (PR). Indeed, the ectopic expression of PR resulted in the inhibition of IFN regulatory factor 3 (IRF-3) phosphorylation and decreased expression of IFN and interferon-stimulated genes. A downregulation of cytoplasmic RIG-I levels occurred in cells undergoing a single-cycle infection with wild-type provirus BH10 but not in cells transfected with a protease-deficient provirus, BH10-PR(-). Cellular fractionation and confocal microscopy studies revealed that RIG-I translocated from the cytosol to an insoluble fraction during the de novo HIV-1 infection of monocyte-derived macrophages, in the presence of PR. The loss of cytoplasmic RIG-I was prevented by the lysosomal inhibitor E64, suggesting that PR targets RIG-I to the lysosomes. This study reveals a novel PR-dependent mechanism employed by HIV-1 to counteract the early IFN response to viral RNA in infected cells. |
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Authors:
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Mayra Solis; Peyman Nakhaei; Mohammad Jalalirad; Judith Lacoste; Renée Douville; Meztli Arguello; Tiejun Zhao; Michael Laughrea; Mark A Wainberg; John Hiscott |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-17 |
Journal Detail:
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Title: Journal of virology Volume: 85 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-13 Completed Date: 2011-02-16 Revised Date: 2011-08-03 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 1224-36 Citation Subset: IM |
Affiliation:
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Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cells, Cultured DEAD-box RNA Helicases / antagonists & inhibitors* HIV Protease / metabolism* HIV-1 / immunology*, pathogenicity* Humans Immune Evasion* Interferon Regulatory Factor-3 / antagonists & inhibitors Interferons / antagonists & inhibitors*, immunology Macrophages / immunology, virology Protein Binding RNA, Viral / immunology Signal Transduction* |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Interferon Regulatory Factor-3; 0/RNA, Viral; 9008-11-1/Interferons; EC 3.4.23.-/HIV Protease; EC 3.4.23.-/p16 protease, Human immunodeficiency virus 1; EC 3.6.1.-/DDX58 protein, human; EC 3.6.1.-/DEAD-box RNA Helicases |
| Comments/Corrections | |
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