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Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model.

ABSTRACT: 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 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' untranslated regions. We used site-directed and random mutagenesis to determine that only the first of the two microRNA-122 seed sites in the viral 5' untranslated region 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 to induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation, and macrovesicular and microvesicular 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 therapy, sofosbuvir, effectively suppresses chronic RHV-rn1 infection in rats. CONCLUSION: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. (Hepatology 2018).

SUBMITTER: Trivedi S

PROVIDER: S-EPMC5832584 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model.

Trivedi Sheetal S Murthy Satyapramod S Sharma Himanshu H Hartlage Alex S AS Kumar Arvind A Gadi Sashi V SV Simmonds Peter P Chauhan Lokendra V LV Scheel Troels K H TKH Billerbeck Eva E Burbelo Peter D PD Rice Charles M CM Lipkin W Ian WI Vandegrift Kurt K Cullen John M JM Kapoor Amit A

Hepatology (Baltimore, Md.) 20180521 2

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 from wild rats (Rattus norvegicus), RHV-rn1; acquired the complete viral genome sequence; and developed an infectious reve ...[more]

PMID: 28859226

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Project description:AIM:To investigate the evaluation of hepatitis C virus (HCV) quasispecies in the envelope region and its relationship with the outcome of acute hepatitis C. METHODS:HCV quasispecies were characterized in specimens collected every 2-6 mo from a cohort of acutely HCV-infected subjects. We evaluated two individuals who spontaneously cleared viremia and three individuals with persistent viremia by cloning 33 1-kb amplicons that spanned E1 and the 5' half of E2, including hypervariable region 1 (HVR1). To assess the quasispecies complexity and to detect variants for sequencing, 33 cloned cDNAs representing each specimen were assessed by a combined method of analysis of a single-stranded conformational polymorphism and heteroduplex analysis. The rates of both synonymous and nonsynonymous substitutions for the E1, HVR1 and E2 regions outside HVR1 were analyzed. RESULTS:Serum samples collected from chronic phase of infection had higher quasispecies complexity than those collected from acute phase of infection in all individuals examined. The genetic diversity (genetic distance) within HVR1 was consistently higher than that in the complete E1 (0.0322+/-0.0068 vs -0.0020+/-0.0014, P<0.05) and E2 regions outside HVR1 (0.0322+/-0.0068 vs 0.0017+/-0.0011, P<0.05) in individuals with persistent viremia, but did not change markedly over time in those with clearance of viremia. For individuals with persistent viremia, the rate of nonsynonymous substitutions within the HVR1 region (2.76X10(-3)+/-1.51X10(-3)) predominated and gradually increased, as compared with that in the E1 and E2 regions outside HVR1 (0.23X10(-3)+/-0.15X10(-3), 0.50X10(-3)+/-0.10X10(-3)). By contrast, the rates of both nonsynonymous and synonymous substitutions for the E1 and E2 regions including HVR1 were consistently lower in individuals with clearance of viremia. CONCLUSION:HCV persistence is associated with a complexity quasispecies and positive selection of HVR1 by the host immune system.

Dataset Information

Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model.

Publications

Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model.

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