Article open access publication

Characterization of nonprimate hepacivirus and construction of a functional molecular clone

Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences, ISSN 0027-8424

Volume 112, 7, 2015

DOI:10.1073/pnas.1500265112, Dimensions: pub.1041710769, PMC: PMC4343093, PMID: 25646476,

Affiliations

Organisations

  1. (1) Copenhagen Hepatitis C Program, Department of Infectious Disease and Clinical Research Centre, Copenhagen University Hospital, DK-2650 Hvidovre, Denmark;
  2. (2) University of Copenhagen, grid.5254.6, KU
  3. (3) Rockefeller University, grid.134907.8
  4. (4) Columbia University, grid.21729.3f
  5. (5) Department of Biomedical Sciences, Edward Via College of Osteopathic Medicine, Auburn, AL 36866; and
  6. (6) Virology Laboratory, Animal Health Diagnostic Center,
  7. (7) Department of Biomedical Sciences,
  8. (8) Baker Institute for Animal Health, and
  9. (9) Cornell University, grid.5386.8

Description

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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University of Copenhagen

Danish Open Access Indicator

2015: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2015: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 63

Field Citation Ratio (FCR): 12.07

Relative Citation ratio (RCR): 2.89

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