Walter, S, Bollenbach, A, Doerrbecker, J et al. (11 more authors) (2016) Ion-channel function and cross-species determinants in viral assembly of nonprimate hepacivirus p7. Journal of Virology, 90 (10). pp. 5075-5089. ISSN 0022-538X
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Editors: |
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Copyright, Publisher and Additional Information: | © 2016, American Society for Microbiology. This is an author produced version of a paper published in the Journal of Virology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | hepatitis C virus; p7; nonprimate hepacivirus; equine hepacivirus; ion-channel |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Oncology and Cancer Research - Labs (Leeds) |
Funding Information: | Funder Grant number Pfizer FELLOWSHIP S. GRIFFIN Pfizer NOT GIVEN |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Mar 2016 15:29 |
Last Modified: | 24 Oct 2016 23:20 |
Published Version: | https://dx.doi.org/10.1128/JVI.00132-16 |
Status: | Published |
Publisher: | American Society for Microbiology |
Identification Number: | 10.1128/JVI.00132-16 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:96296 |