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

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

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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).

Original languageEnglish (US)
Pages (from-to)435-448
Number of pages14
JournalHepatology
Volume68
Issue number2
DOIs
StatePublished - Aug 1 2018

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Hepatitis Viruses
Hepacivirus
Liver Diseases
5' Untranslated Regions
Virus Diseases
Immunity
Animal Hepatitis
Inbred Strains Rats
Reverse Genetics
Polyproteins
Viral Structures
Viral Genome
Liver
3' Untranslated Regions
Gastroenterology
Site-Directed Mutagenesis
Infection
MicroRNAs
Interferons
Antiviral Agents

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Trivedi, S., Murthy, S., Sharma, H., Hartlage, A. S., Kumar, A., Gadi, S. V., ... Kapoor, A. (2018). Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model. Hepatology, 68(2), 435-448. https://doi.org/10.1002/hep.29494
Trivedi, Sheetal ; Murthy, Satyapramod ; Sharma, Himanshu ; Hartlage, Alex S. ; Kumar, Arvind ; Gadi, Sashi V. ; Simmonds, Peter ; Chauhan, Lokendra V. ; Scheel, Troels K.H. ; Billerbeck, Eva ; Burbelo, Peter D. ; Rice, Charles M. ; Lipkin, W. Ian ; Vandegrift, Kurt ; Cullen, John M. ; Kapoor, Amit. / Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model. In: Hepatology. 2018 ; Vol. 68, No. 2. pp. 435-448.
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Trivedi, S, Murthy, S, Sharma, H, Hartlage, AS, Kumar, A, Gadi, SV, Simmonds, P, Chauhan, LV, Scheel, TKH, Billerbeck, E, Burbelo, PD, Rice, CM, Lipkin, WI, Vandegrift, K, Cullen, JM & Kapoor, A 2018, 'Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model', Hepatology, vol. 68, no. 2, pp. 435-448. https://doi.org/10.1002/hep.29494

Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model. / Trivedi, Sheetal; Murthy, Satyapramod; Sharma, Himanshu; Hartlage, Alex S.; Kumar, Arvind; Gadi, Sashi V.; Simmonds, Peter; Chauhan, Lokendra V.; Scheel, Troels K.H.; Billerbeck, Eva; Burbelo, Peter D.; Rice, Charles M.; Lipkin, W. Ian; Vandegrift, Kurt; Cullen, John M.; Kapoor, Amit.

In: Hepatology, Vol. 68, No. 2, 01.08.2018, p. 435-448.

Research output: Contribution to journalArticle

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AU - Trivedi, Sheetal

AU - Murthy, Satyapramod

AU - Sharma, Himanshu

AU - Hartlage, Alex S.

AU - Kumar, Arvind

AU - Gadi, Sashi V.

AU - Simmonds, Peter

AU - Chauhan, Lokendra V.

AU - Scheel, Troels K.H.

AU - Billerbeck, Eva

AU - Burbelo, Peter D.

AU - Rice, Charles M.

AU - Lipkin, W. Ian

AU - Vandegrift, Kurt

AU - Cullen, John M.

AU - Kapoor, Amit

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N2 - 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).

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Trivedi S, Murthy S, Sharma H, Hartlage AS, Kumar A, Gadi SV et al. Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model. Hepatology. 2018 Aug 1;68(2):435-448. https://doi.org/10.1002/hep.29494