Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus
The restricted host tropism of hepatitis C virus (HCV) remains incompletely understood, especially post-entry, and has hindered developing an immunocompetent, small animal model. HCV replication in non-permissive species may be limited by incompatibilities between the viral replication machinery and...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/44436 |
| _version_ | 1811236930689433600 |
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| author | Jenna M Gaska Metodi Balev Qiang Ding Brigitte Heller Alexander Ploss |
| author_facet | Jenna M Gaska Metodi Balev Qiang Ding Brigitte Heller Alexander Ploss |
| author_sort | Jenna M Gaska |
| collection | DOAJ |
| description | The restricted host tropism of hepatitis C virus (HCV) remains incompletely understood, especially post-entry, and has hindered developing an immunocompetent, small animal model. HCV replication in non-permissive species may be limited by incompatibilities between the viral replication machinery and orthologs of essential host factors, like cyclophilin A (CypA). We thus compared the ability of CypA from mouse, tree shrew, and seven non-human primate species to support HCV replication, finding that murine CypA only partially rescued viral replication in Huh7.5-shRNA CypA cells. We determined the specific amino acid differences responsible and generated mutants able to fully rescue replication. We expressed these mutants in engineered murine hepatoma cells and although we observed increases in HCV replication following infection, they remained far lower than those in highly permissive human hepatoma cells, and minimal infectious particle release was observed. Together, these data suggest additional co-factors remain unidentified. Future work to determine such factors will be critical for developing an immunocompetent mouse model supporting HCV replication. |
| first_indexed | 2024-04-12T12:16:34Z |
| format | Article |
| id | doaj.art-3f20b41a2f924998a2ea491a773599b0 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:16:34Z |
| publishDate | 2019-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3f20b41a2f924998a2ea491a773599b02022-12-22T03:33:24ZengeLife Sciences Publications LtdeLife2050-084X2019-05-01810.7554/eLife.44436Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virusJenna M Gaska0https://orcid.org/0000-0003-1706-9701Metodi Balev1Qiang Ding2Brigitte Heller3Alexander Ploss4https://orcid.org/0000-0001-9322-7252Department of Molecular Biology, Princeton University, Princeton, United StatesDepartment of Molecular Biology, Princeton University, Princeton, United StatesDepartment of Molecular Biology, Princeton University, Princeton, United StatesDepartment of Molecular Biology, Princeton University, Princeton, United StatesDepartment of Molecular Biology, Princeton University, Princeton, United StatesThe restricted host tropism of hepatitis C virus (HCV) remains incompletely understood, especially post-entry, and has hindered developing an immunocompetent, small animal model. HCV replication in non-permissive species may be limited by incompatibilities between the viral replication machinery and orthologs of essential host factors, like cyclophilin A (CypA). We thus compared the ability of CypA from mouse, tree shrew, and seven non-human primate species to support HCV replication, finding that murine CypA only partially rescued viral replication in Huh7.5-shRNA CypA cells. We determined the specific amino acid differences responsible and generated mutants able to fully rescue replication. We expressed these mutants in engineered murine hepatoma cells and although we observed increases in HCV replication following infection, they remained far lower than those in highly permissive human hepatoma cells, and minimal infectious particle release was observed. Together, these data suggest additional co-factors remain unidentified. Future work to determine such factors will be critical for developing an immunocompetent mouse model supporting HCV replication.https://elifesciences.org/articles/44436Hepatitis C virusspecies tropismanimal model |
| spellingShingle | Jenna M Gaska Metodi Balev Qiang Ding Brigitte Heller Alexander Ploss Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus eLife Hepatitis C virus species tropism animal model |
| title | Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus |
| title_full | Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus |
| title_fullStr | Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus |
| title_full_unstemmed | Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus |
| title_short | Differences across cyclophilin A orthologs contribute to the host range restriction of hepatitis C virus |
| title_sort | differences across cyclophilin a orthologs contribute to the host range restriction of hepatitis c virus |
| topic | Hepatitis C virus species tropism animal model |
| url | https://elifesciences.org/articles/44436 |
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