title: Cyclophilin Inhibitors Remodel the Endoplasmic Reticulum of HCV-Infected Cells in a Unique Pattern Rendering Cells Impervious to a Reinfection.
abstract: The mechanisms of action by which cyclophilin inhibitors (CypI) interfere with the HCV life cycle remain poorly understood. We reported that CypI and NS5A inhibitors (NS5Ai), but not other classes of anti-HCV agents, prevent assembly of double membrane vesicles (DMVs), which protect replication complexes. We demonstrated that both NS5A and the isomerase cyclophilin A (CypA) are required for DMV formation. Here, we examined whether CypI mediate an additional antiviral effect that could further explain the high efficacy of CypI. We identified a unique action of CypI. CypI remodel the organization of the endoplasmic reticulum (ER) of HCV-infected cells, but not of uninfected cells. This effect is specific since it was not observed for other classes of anti-HCV agents including NS5Ai, and has no effect on the viability of CypI-treated cells. Since ER serves as platform for the establishment of HCV replication complexes, we asked whether the ER reorganization by CypI would prevent cells from being newly infected. Remarkably, CypI-treated HCV-pre-infected cells remain totally impervious to a reinfection, suggesting that the CypI-mediated ER reorganization prevents a reinfection. This block is not due to residual CypI since CypI-resistant HCV variants also fail to infect these cells. The ER reorganization by CypI is rapid and reversible. This study provides the first evidence that CypI trigger a unique ER reorganization of infected cells, rendering cells transiently impervious to a reinfection. This study further suggests that the HCV-induced ER rearrangement represents a key target for the development of new therapies.
authors.affiliation: Department of Immunology & Microbial Science The Scripps Research Institute, La Jolla, California, 92037, United States of America.
authors.forename: Udayan
authors.initials: U
authors.lastname: Chatterji
authors.affiliation: Department of Immunology & Microbial Science The Scripps Research Institute, La Jolla, California, 92037, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bobardt
authors.affiliation: DNA Array Core Facility, The Scripps Rese6arch Institute, La Jolla, California, 92037, United States of America.
authors.forename: Lana
authors.initials: L
authors.lastname: Schaffer
authors.affiliation: Department of Immunology & Microbial Science The Scripps Research Institute, La Jolla, California, 92037, United States of America.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Wood
authors.affiliation: Department of Immunology & Microbial Science The Scripps Research Institute, La Jolla, California, 92037, United States of America.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Gallay
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000473:pathology / Q000821:virology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007700:Kinetics; D000069474:Sofosbuvir / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D021983:Cyclophilins; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D000069474:Sofosbuvir; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C499715:alisporivir