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Home / Equine Research Bank / Proc Natl Acad Sci U S A / Characterization of nonprimate hepacivirus and construction ...
Proceedings of the National Academy of Sciences of the United States of America2015; 112(7); 2192-2197; doi: 10.1073/pnas.1500265112

Characterization of nonprimate hepacivirus and construction of a functional molecular clone.

Abstract: Nonprimate hepacivirus (NPHV) is the closest known relative of hepatitis C virus (HCV) and its study could enrich our understanding of HCV evolution, immunity, and pathogenesis. High seropositivity is found in horses worldwide with ∼ 3% viremic. NPHV natural history and molecular virology remain largely unexplored, however. Here, we show that NPHV, like HCV, can cause persistent infection for over a decade, with high titers and negative strand RNA in the liver. NPHV is a near-universal contaminant of commercial horse sera for cell culture. The complete NPHV 3'-UTR was determined and consists of interspersed homopolymer tracts and an HCV-like 3'-terminal poly(U)-X-tail. NPHV translation is stimulated by miR-122 and the 3'-UTR and, similar to HCV, the NPHV NS3-4A protease can cleave mitochondrial antiviral-signaling protein to inactivate the retinoic acid-inducible gene I pathway. Using an NPHV consensus cDNA clone, replication was not observed in primary equine fetal liver cultures or after electroporation of selectable replicons. However, intrahepatic RNA inoculation of a horse initiated infection, yielding high RNA titers in the serum and liver. Delayed seroconversion, slightly elevated circulating liver enzymes and mild hepatitis was observed, followed by viral clearance. This establishes the molecular components of a functional NPHV genome. Thus, NPHV appears to resemble HCV not only in genome structure but also in its ability to establish chronic infection with delayed seroconversion and hepatitis. This NPHV infectious clone and resulting acute phase sera will facilitate more detailed studies on the natural history, pathogenesis, and immunity of this novel hepacivirus in its natural host.
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Publication Date: 2015-02-02 PubMed ID: 25646476PubMed Central: PMC4343093DOI: 10.1073/pnas.1500265112Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates the nonprimate hepacivirus (NPHV), a relative of hepatitis C virus (HCV), and its characteristics, including its ability to cause long-term infection, genome structure, and connection to certain diseases. The study also creates a functional NPHV genome, which can directly infect and cause disease in horses, further aiding in the detailed understanding of this virus.

The Nature and Characteristics of Nonprimate Hepacivirus (NPHV)

  • The research found that the NPHV can lead to persistent infections that last over a decade, similar to the Hepatitis C virus (HCV).
  • NPHV leaves high titers and negative strand RNA in the liver. The high prevalence of this virus has caused it to be a common contaminant in horse sera, a commercial product used in cell culture.
  • The complete NPHV 3′-UTR — the untranslated region at the end of the viral genome — was identified and found to consist of interspersed homopolymer tracts and an HCV-like 3′-terminal poly(U)-X-tail. This mosaic-like structure is similar to that of HCV, demonstrating an evolutionary link between the two viruses.

NPHV’s Impact and Relationship with miR-122 and the 3′-UTR

  • NPHV stimulates translation using miR-122 (a microRNA important for liver function) and the 3′-UTR. This is again similar to HCV which also uses these elements to replicate itself.
  • NPHV NS3-4A protease, to like HCV, can cleave or ‘cut’ the mitochondrial antiviral-signaling protein. This process inactivates the retinoic-acid inducible gene I pathway, involved in immune response, potentially demonstrating how NPHV evades the immune system and leads to chronic infection.

Construction of a Functional NPHV Genome

  • While initial attempts to demonstrate replication using a consensus NPHV cDNA clone were not successful in primary equine fetal liver cultures or electroporation of selectable replicons, intrahepatic RNA inoculation of a horse initiated infection. This suggests that infection can occur naturally in horses but requires specific conditions to take place in a laboratory setting.
  • Infection in the horse led to high RNA titers in the serum and liver, mild hepatitis, and slightly elevated circulating liver enzymes. There was also a delay in seroconversion (the point at which antibodies against the virus become detectable), another characteristic common to HCV, before eventual viral clearance.

Implications and Future Directions

  • These findings not only expand our understanding of NPHV but also offer potential insights into the structure and behavior of HCV given their similarities. The creation of a functional NPHV genome serves as a helpful tool for furthering virus research, particularly into the natural history, pathogenesis, and immunity of the hepacivirus in its natural host, the horse.

Cite This Article

APA
Scheel TK, Kapoor A, Nishiuchi E, Brock KV, Yu Y, Andrus L, Gu M, Renshaw RW, Dubovi EJ, McDonough SP, Van de Walle GR, Lipkin WI, Divers TJ, Tennant BC, Rice CM. (2015). Characterization of nonprimate hepacivirus and construction of a functional molecular clone. Proc Natl Acad Sci U S A, 112(7), 2192-2197. https://doi.org/10.1073/pnas.1500265112

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 112
Issue: 7
Pages: 2192-2197

Researcher Affiliations

Scheel, Troels K H
  • Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065; Copenhagen Hepatitis C Program, Department of Infectious Disease and Clinical Research Centre, Copenhagen University Hospital, DK-2650 Hvidovre, Denmark; Department of International Health, Immunology, and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark;
Kapoor, Amit
  • Center for Infection and Immunity, Columbia University, New York, NY 10032;
Nishiuchi, Eiko
  • Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065;
Brock, Kenny V
  • Department of Biomedical Sciences, Edward Via College of Osteopathic Medicine, Auburn, AL 36866; and.
Yu, Yingpu
  • Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065;
Andrus, Linda
  • Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065;
Gu, Meigang
  • Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065;
Renshaw, Randall W
  • Virology Laboratory, Animal Health Diagnostic Center.
Dubovi, Edward J
  • Virology Laboratory, Animal Health Diagnostic Center.
McDonough, Sean P
  • Department of Biomedical Sciences.
Van de Walle, Gerlinde R
  • Baker Institute for Animal Health, and.
Lipkin, W Ian
  • Center for Infection and Immunity, Columbia University, New York, NY 10032;
Divers, Thomas J
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
Tennant, Bud C
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
Rice, Charles M
  • Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065; ricec@rockefeller.edu.

MeSH Terms

  • 3' Untranslated Regions
  • Cloning, Molecular
  • DNA, Complementary
  • Hepacivirus / genetics
  • Hepacivirus / physiology
  • Molecular Sequence Data
  • Protein Biosynthesis
  • Viral Load
  • Virus Replication

Grant Funding

  • UL1 TR000043 / NCATS NIH HHS
  • R01 AI072613 / NIAID NIH HHS
  • UL1RR024143 / NCRR NIH HHS
  • R01 DK085713 / NIDDK NIH HHS
  • CA057973 / NCI NIH HHS
  • UL1 RR024143 / NCRR NIH HHS
  • AI107631 / NIAID NIH HHS
  • R21 AI107631 / NIAID NIH HHS
  • AI072613 / NIAID NIH HHS
  • DK085713 / NIDDK NIH HHS
  • R01 CA057973 / NCI NIH HHS

Conflict of Interest Statement

The authors declare no conflict of interest.

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