title: Impaired expression of type I and type II interferon receptors in HCV-associated chronic liver disease and liver cirrhosis.
abstract: OBJECTIVE
  Chronic Hepatitis C Virus (HCV)-infected patients with liver cirrhosis (LC) respond poorly to interferon-alpha (IFN-α) and ribavirin (RBV) combination therapy, but the reason for this is unclear. We previously reported that HCV-infection induces endoplasmic reticulum (ER) stress and autophagy response that selectively down regulates the type I IFN-α receptor-1 (IFNAR1) and RBV transporters (CNT1 and ENT1), leading to IFN-α/RBV resistance. The goal of this study is to verify whether an increase in ER stress and autophagy response is also associated with the reduced expression of IFNAR1 and RBV transporters in chronic HCV-infected patients.
  
  
  METHODS
  Primary human hepatocytes (PHH) were infected with cell culture grown HCV particles (JFH-ΔV3-Rluc). HCV replication was confirmed by the detection of viral RNA by RT-qPCR and HCV-core protein by Western blotting. The ER stress and autophagy response and expression of IFN receptors and RBV transporters in HCV infected PHH and liver tissues derived from patients were measured by Western blotting.
  
  
  RESULTS
  HCV infection of PHH showed impaired expression of IFNAR1, IFNγR1 (Type II IFN receptor) and RBV transporters but not IL10Rβ (Type III IFN-λ receptor). ER stress markers (BiP, IRE1α and peIF2α) and autophagy response (LC3II, Beclin 1 and ATG5) were induced in HCV infected chronic liver disease (CLD) and LC patients. Liver biopsies (CLD) show a 50% reduced expression of IFNAR1 and RBV transporters. Furthermore, the expression of IFNAR1 and RBV transporters was impaired in almost all LC patients.
  
  
  CONCLUSIONS
  HCV infection induces ER stress and autophagy response in infected PHH and chronically infected liver tissues. The expression of IFNAR1, IFNγR1 and RBV transporters were significantly impaired in CLD and cirrhotic livers. Our study provides a potential explanation for the reduced response rate of IFN-α and RBV combination therapy in HCV infected patients with liver cirrhosis.
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Partha K
authors.initials: PK
authors.lastname: Chandra
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Feyza
authors.initials: F
authors.lastname: Gunduz
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Hazari
authors.affiliation: Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Ramazan
authors.initials: R
authors.lastname: Kurt
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Panigrahi
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Bret
authors.initials: B
authors.lastname: Poat
authors.affiliation: Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Bruce
authors.affiliation: Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Cohen
authors.forename: Humberto E
authors.initials: HE
authors.lastname: Bohorquez
authors.affiliation: Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America.
authors.forename: Humberto E
authors.initials: HE
authors.lastname: Behorquez
authors.affiliation: Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Carmody
authors.affiliation: Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Loss
authors.affiliation: Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Balart
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America; Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Dash
mesh_terms: D001343:Autophagy; D001692:Biological Transport; D001706:Biopsy; D002478:Cells, Cultured; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D000431:Ethanol / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism*; D012254:Ribavirin; D014779:Virus Replication
chemical_list: D005230:Fatty Acids, Nonesterified; D017471:Receptors, Interferon; C120411:interferon receptor, type II; D053633:Receptor, Interferon alpha-beta; D000431:Ethanol; D012254:Ribavirin