Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Viral persistence, liver disease and host response in Hepatitis C-like virus rat model

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Letter to the Editor: Glucocorticosteroids for Alcohol-Associated Hepatitis

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. PNPLA3 genotype and risk of liver and all-cause mortality

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase-Lowering Effect of a HSD17B13 Variant

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Abstracts

    Publikation: Bidrag til tidsskriftKonferenceabstrakt i tidsskriftForskningpeer review

  1. Equine pegiviruses cause persistent infection of bone marrow and are not associated with hepatitis

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Evolutionary selection of pestivirus variants with altered or no microRNA dependency

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Replicons of a rodent hepatitis C model virus permit selection of highly permissive cells

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Functional Interplay between RNA Viruses and Non-Coding RNA in Mammals

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

  5. Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Sheetal Trivedi
  • Satyapramod Murthy
  • Himanshu Sharma
  • Alex S Hartlage
  • Arvind Kumar
  • Sashi Gadi
  • Peter Simmonds
  • Lokendra V Chauhan
  • Troels K H Scheel
  • Eva Billerbeck
  • Peter D Burbelo
  • Charles M Rice
  • W Ian Lipkin
  • Kurt Vandergrift
  • John M Cullen
  • Amit Kapoor
Vis graf over relationer

The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus (RHV) from wild rats (Rattus norvegicus), RHV-rn1, acquired the complete viral genome sequence and developed an infectious reverse genetics system. RHV-rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5' and 3' UTRs. We used site-directed and random mutagenesis to determine that only the first of the two miR-122 seed sites in viral 5'UTR is required for viral replication and persistence in rats. Next, we used the clone derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV-rn1 possesses several HCV-defining hallmarks: hepatotropism, propensity to persist, and the ability of induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation and macro/micro vesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV-rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct acting antiviral (DAA) therapy, Sofosbuvir, effectively suppresses chronic RHV-rn1 infection in rats. Taken together, we developed RHV-rn1 infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV-related viral persistence, immunity and pathogenesis. This article is protected by copyright. All rights reserved.

OriginalsprogEngelsk
TidsskriftHepatology (Baltimore, Md.)
Vol/bind68
Udgave nummer2
Sider (fra-til)435-448
ISSN0270-9139
DOI
StatusUdgivet - 1 aug. 2018

ID: 51663950