Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle.
Recent functional genomics studies including genome-wide small interfering RNA (siRNA) screens demonstrated that hepatitis C virus (HCV) exploits an extensive network of host factors for productive infection and propagation. How these co-opted host functions interact with various steps of HCV replic...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004163&type=printable |
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| author | Qisheng Li Yong-Yuan Zhang Stephan Chiu Zongyi Hu Keng-Hsin Lan Helen Cha Catherine Sodroski Fang Zhang Ching-Sheng Hsu Emmanuel Thomas T Jake Liang |
| author_facet | Qisheng Li Yong-Yuan Zhang Stephan Chiu Zongyi Hu Keng-Hsin Lan Helen Cha Catherine Sodroski Fang Zhang Ching-Sheng Hsu Emmanuel Thomas T Jake Liang |
| author_sort | Qisheng Li |
| collection | DOAJ |
| description | Recent functional genomics studies including genome-wide small interfering RNA (siRNA) screens demonstrated that hepatitis C virus (HCV) exploits an extensive network of host factors for productive infection and propagation. How these co-opted host functions interact with various steps of HCV replication cycle and exert pro- or antiviral effects on HCV infection remains largely undefined. Here we present an unbiased and systematic strategy to functionally interrogate HCV host dependencies uncovered from our previous infectious HCV (HCVcc) siRNA screen. Applying functional genomics approaches and various in vitro HCV model systems, including HCV pseudoparticles (HCVpp), single-cycle infectious particles (HCVsc), subgenomic replicons, and HCV cell culture systems (HCVcc), we identified and characterized novel host factors or pathways required for each individual step of the HCV replication cycle. Particularly, we uncovered multiple HCV entry factors, including E-cadherin, choline kinase α, NADPH oxidase CYBA, Rho GTPase RAC1 and SMAD family member 6. We also demonstrated that guanine nucleotide binding protein GNB2L1, E2 ubiquitin-conjugating enzyme UBE2J1, and 39 other host factors are required for HCV RNA replication, while the deubiquitinating enzyme USP11 and multiple other cellular genes are specifically involved in HCV IRES-mediated translation. Families of antiviral factors that target HCV replication or translation were also identified. In addition, various virologic assays validated that 66 host factors are involved in HCV assembly or secretion. These genes included insulin-degrading enzyme (IDE), a proviral factor, and N-Myc down regulated Gene 1 (NDRG1), an antiviral factor. Bioinformatics meta-analyses of our results integrated with literature mining of previously published HCV host factors allows the construction of an extensive roadmap of cellular networks and pathways involved in the complete HCV replication cycle. This comprehensive study of HCV host dependencies yields novel insights into viral infection, pathogenesis and potential therapeutic targets. |
| format | Article |
| id | doaj-art-ea7c2c8aab0548ecb443dce93dc855c6 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-ea7c2c8aab0548ecb443dce93dc855c62025-08-20T02:22:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-05-01105e100416310.1371/journal.ppat.1004163Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle.Qisheng LiYong-Yuan ZhangStephan ChiuZongyi HuKeng-Hsin LanHelen ChaCatherine SodroskiFang ZhangChing-Sheng HsuEmmanuel ThomasT Jake LiangRecent functional genomics studies including genome-wide small interfering RNA (siRNA) screens demonstrated that hepatitis C virus (HCV) exploits an extensive network of host factors for productive infection and propagation. How these co-opted host functions interact with various steps of HCV replication cycle and exert pro- or antiviral effects on HCV infection remains largely undefined. Here we present an unbiased and systematic strategy to functionally interrogate HCV host dependencies uncovered from our previous infectious HCV (HCVcc) siRNA screen. Applying functional genomics approaches and various in vitro HCV model systems, including HCV pseudoparticles (HCVpp), single-cycle infectious particles (HCVsc), subgenomic replicons, and HCV cell culture systems (HCVcc), we identified and characterized novel host factors or pathways required for each individual step of the HCV replication cycle. Particularly, we uncovered multiple HCV entry factors, including E-cadherin, choline kinase α, NADPH oxidase CYBA, Rho GTPase RAC1 and SMAD family member 6. We also demonstrated that guanine nucleotide binding protein GNB2L1, E2 ubiquitin-conjugating enzyme UBE2J1, and 39 other host factors are required for HCV RNA replication, while the deubiquitinating enzyme USP11 and multiple other cellular genes are specifically involved in HCV IRES-mediated translation. Families of antiviral factors that target HCV replication or translation were also identified. In addition, various virologic assays validated that 66 host factors are involved in HCV assembly or secretion. These genes included insulin-degrading enzyme (IDE), a proviral factor, and N-Myc down regulated Gene 1 (NDRG1), an antiviral factor. Bioinformatics meta-analyses of our results integrated with literature mining of previously published HCV host factors allows the construction of an extensive roadmap of cellular networks and pathways involved in the complete HCV replication cycle. This comprehensive study of HCV host dependencies yields novel insights into viral infection, pathogenesis and potential therapeutic targets.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004163&type=printable |
| spellingShingle | Qisheng Li Yong-Yuan Zhang Stephan Chiu Zongyi Hu Keng-Hsin Lan Helen Cha Catherine Sodroski Fang Zhang Ching-Sheng Hsu Emmanuel Thomas T Jake Liang Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle. PLoS Pathogens |
| title | Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle. |
| title_full | Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle. |
| title_fullStr | Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle. |
| title_full_unstemmed | Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle. |
| title_short | Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle. |
| title_sort | integrative functional genomics of hepatitis c virus infection identifies host dependencies in complete viral replication cycle |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004163&type=printable |
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