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Journal of virology2016; 90(10); 5075-5089; doi: 10.1128/JVI.00132-16

Ion Channel Function and Cross-Species Determinants in Viral Assembly of Nonprimate Hepacivirus p7.

Abstract: Nonprimate hepacivirus (NPHV), the closest homolog of hepatitis C virus (HCV) described to date, has recently been discovered in horses. Even though the two viruses share a similar genomic organization, conservation of the encoded hepaciviral proteins remains undetermined. The HCV p7 protein is localized within endoplasmic reticulum (ER) membranes and is important for the production of infectious particles. In this study, we analyzed the structural and functional features of NPHV p7 in addition to its role during virus assembly. Three-dimensional homology models for NPHV p7 using various nuclear magnetic resonance spectroscopy (NMR) structures were generated, highlighting the conserved residues important for ion channel function. By applying a liposome permeability assay, we observed that NPHV p7 exhibited liposome permeability features similar to those of HCV p7, indicative of similar ion channel activity. Next, we characterized the viral protein using a p7-based trans-complementation approach. A similar subcellular localization pattern at the ER membrane was observed, although production of infectious particles was likely hindered by genetic incompatibilities with HCV proteins. To further characterize these cross-species constraints, chimeric viruses were constructed by substituting different regions of HCV p7 with NPHV p7. The N terminus and transmembrane domains were nonexchangeable and therefore constitute a cross-species barrier in hepaciviral assembly. In contrast, the basic loop and the C terminus of NPHV p7 were readily exchangeable, allowing production of infectious trans-complemented viral particles. In conclusion, comparison of NPHV and HCV p7 revealed structural and functional homology of these proteins, including liposome permeability, and broadly acting determinants that modulate hepaciviral virion assembly and contribute to the host-species barrier were identified. The recent discovery of new relatives of hepatitis C virus (HCV) enables for the first time the study of cross-species determinants shaping hepaciviral pathogenesis. Nonprimate hepacivirus (NPHV) was described to infect horses and represents so far the closest homolog of HCV. Both viruses encode the same viral proteins; however, NPHV protein functions remain poorly understood. In this study, we aimed to dissect NPHV p7 on a structural and functional level. By using various NMR structures of HCV p7 as templates, three-dimensional homology models for NPHV p7 were generated, highlighting conserved residues that are important for ion channel function. A p7-based trans-complementation approach and the construction of NPHV/HCV p7 chimeric viruses showed that the N terminus and transmembrane domains were nonexchangeable. In contrast, the basic loop and the C terminus of NPHV p7 were readily exchangeable, allowing production of infectious viral particles. These results identify species-specific constraints as well as exchangeable determinants in hepaciviral assembly.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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Publication Date: 2016-04-29 PubMed ID: 26962224PubMed Central: PMC4859704DOI: 10.1128/JVI.00132-16Google 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 article explores the structural and functional features of Nonprimate Hepacivirus (NPHV) p7. The study generated three-dimensional models to pinpoint ion channel function and utilized a liposome permeability test to assess similarities to Hepatitis C virus (HCV) p7, revealing species-specific constraints and exchangeable determinants in Hepaciviral assembly.

Introduction and Background

  • The article begins by providing a background on Hepatitis C and Nonprimate Hepacivirus (NPHV). It explains the recognition of NPHV as the closest counterpart to Hepatitis C virus (HCV) found in horses but acknowledges that the conservation of the encoded Hepaciviral proteins remains uncertain.
  • The research highlights the importance of the p7 protein, which is located within the endoplasmic reticulum membranes, to the production of infectious particles.

The Study on NPHV p7

  • The researchers analyzed the structural and functional features of NPHV p7 and its role during virus assembly. They used different nuclear magnetic resonance spectroscopy (NMR) structures to create three-dimensional homology models, showcasing the conserved residues vital for ion channel functionality.
  • The study used a liposome permeability assay and found that the NPHV p7 exhibited similar characteristics to HCV p7 suggesting a similar ion channel activity.

Assessing the Constraints and Determinants in Hepaciviral Assembly

  • To understand the limiting factors affecting the replication abilities between the two species, scientists constructed hybrid versions of the virus by substituting various sections of HCV p7 with NPHV p7.
  • The research found that the N terminus and transmembrane domains of NPHV were not interchangeable with those of HCV, implying a barrier to cross-species Hepaciviral assembly.
  • Conversely, they discovered that the basic loop and the C terminus of NPHV p7 could be easily substituted, allowing for the production of infectious trans-complemented viral particles.

Research Findings and Conclusion

  • Overall, the study found structural and functional similarities between NPHV and HCV p7 proteins, as well as identifying factors that modulate hepaciviral virion assembly and contribute to the host-species barrier.
  • Through these findings, the scientists were able to better understand the cross-species determinants that define hepaciviral pathogenesis.

Cite This Article

APA
Walter S, Bollenbach A, Doerrbecker J, Pfaender S, Brown RJP, Vieyres G, Scott C, Foster R, Kumar A, Zitzmann N, Griffin S, Penin F, Pietschmann T, Steinmann E. (2016). Ion Channel Function and Cross-Species Determinants in Viral Assembly of Nonprimate Hepacivirus p7. J Virol, 90(10), 5075-5089. https://doi.org/10.1128/JVI.00132-16

Publication

Journal of virology
ISSN: 1098-5514
NlmUniqueID: 0113724
Country: United States
Language: English
Volume: 90
Issue: 10
Pages: 5075-5089

Researcher Affiliations

Walter, Stephanie
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Bollenbach, Alexander
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Doerrbecker, Juliane
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Pfaender, Stephanie
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Brown, Richard J P
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Vieyres, Gabrielle
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Scott, Claire
  • Leeds Institute of Cancer & Pathology, University of Leeds, St James' University Hospital, Leeds, Great Britain.
Foster, Richard
  • Leeds Institute of Cancer & Pathology, University of Leeds, St James' University Hospital, Leeds, Great Britain.
Kumar, Abhinav
  • Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, Great Britain.
Zitzmann, Nicole
  • Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, Great Britain.
Griffin, Stephen
  • Leeds Institute of Cancer & Pathology, University of Leeds, St James' University Hospital, Leeds, Great Britain.
Penin, François
  • Institut de Biologie et Chimie des Protéines, CNRS, UMR 5086, Laboratoire International Associé CNRS-UIUC, Labex Ecofect, University of Lyon, Lyon, France.
Pietschmann, Thomas
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany.
Steinmann, Eike
  • Institute for Experimental Virology, TWINCORE, Hannover, Germany Eike.Steinmann@twincore.de.

MeSH Terms

  • Animals
  • Cell Line
  • Endoplasmic Reticulum / metabolism
  • Genetic Complementation Test
  • Hepacivirus / chemistry
  • Hepacivirus / genetics
  • Hepacivirus / physiology
  • Horses
  • Humans
  • Ion Channels / chemistry
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Liposomes
  • Models, Molecular
  • Permeability
  • Species Specificity
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Assembly
  • Virus Replication

Grant Funding

  • G0700124 / Medical Research Council
  • MC_PC_13066 / Medical Research Council

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Citations

This article has been cited 4 times.
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