title: RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I.
abstract: 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.
authors.affiliation: Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Mayra
authors.initials: M
authors.lastname: Solis
authors.forename: Peyman
authors.initials: P
authors.lastname: Nakhaei
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jalalirad
authors.forename: Judith
authors.initials: J
authors.lastname: Lacoste
authors.forename: Renée
authors.initials: R
authors.lastname: Douville
authors.forename: Meztli
authors.initials: M
authors.lastname: Arguello
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Laughrea
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D011485:Protein Binding; D012367:RNA, Viral / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction
chemical_list: D050838:Interferon Regulatory Factor-3; D012367:RNA, Viral; D011971:Receptors, Immunologic; D007372:Interferons; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases