Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin
Hepatitis E virus (HEV) is increasingly recognized as the leading cause of acute hepatitis. Although HEV infections are mostly self-limiting, a chronic course can develop especially in those with immunocompromised state. Ribavirin is currently used to treat such patients. According to various report...
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MDPI AG
2022-11-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/11/2440 |
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| author | Putu Prathiwi Primadharsini Shigeo Nagashima Masaharu Takahashi Kazumoto Murata Hiroaki Okamoto |
| author_facet | Putu Prathiwi Primadharsini Shigeo Nagashima Masaharu Takahashi Kazumoto Murata Hiroaki Okamoto |
| author_sort | Putu Prathiwi Primadharsini |
| collection | DOAJ |
| description | Hepatitis E virus (HEV) is increasingly recognized as the leading cause of acute hepatitis. Although HEV infections are mostly self-limiting, a chronic course can develop especially in those with immunocompromised state. Ribavirin is currently used to treat such patients. According to various reports on chronic HEV infections, a sustained virological response (SVR) was achieved in approximately 80% of patients receiving ribavirin monotherapy. To increase the SVR rate, drug combination might be a viable strategy, which we attempted in the current study. Ritonavir was identified in our previous drug screening while searching for candidate novel anti-HEV drugs. It demonstrated potent inhibition of HEV growth in cultured cells. In the present study, ritonavir blocked HEV internalization as shown through time-of-addition and immunofluorescence assays. Its combination with ribavirin significantly increased the efficiency of inhibiting HEV growth compared to that shown by ribavirin monotherapy, even in PLC/PRF/5 cells with robust HEV production, and resulted in viral clearance. Similar efficiency was seen for HEV genotypes 3 and 4, the main causes of chronic infection. The present findings provide insight concerning the advantage of combination therapy using drugs blocking different steps in the HEV life cycle (internalization and RNA replication) as a potential novel treatment strategy for chronic hepatitis E. |
| first_indexed | 2024-03-09T18:34:31Z |
| format | Article |
| id | doaj.art-a8c5851ba8034049a0e6d8fc1441da5b |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T18:34:31Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-a8c5851ba8034049a0e6d8fc1441da5b2023-11-24T07:17:15ZengMDPI AGViruses1999-49152022-11-011411244010.3390/v14112440Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with RibavirinPutu Prathiwi Primadharsini0Shigeo Nagashima1Masaharu Takahashi2Kazumoto Murata3Hiroaki Okamoto4Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, JapanDivision of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, JapanDivision of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, JapanDivision of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, JapanDivision of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, JapanHepatitis E virus (HEV) is increasingly recognized as the leading cause of acute hepatitis. Although HEV infections are mostly self-limiting, a chronic course can develop especially in those with immunocompromised state. Ribavirin is currently used to treat such patients. According to various reports on chronic HEV infections, a sustained virological response (SVR) was achieved in approximately 80% of patients receiving ribavirin monotherapy. To increase the SVR rate, drug combination might be a viable strategy, which we attempted in the current study. Ritonavir was identified in our previous drug screening while searching for candidate novel anti-HEV drugs. It demonstrated potent inhibition of HEV growth in cultured cells. In the present study, ritonavir blocked HEV internalization as shown through time-of-addition and immunofluorescence assays. Its combination with ribavirin significantly increased the efficiency of inhibiting HEV growth compared to that shown by ribavirin monotherapy, even in PLC/PRF/5 cells with robust HEV production, and resulted in viral clearance. Similar efficiency was seen for HEV genotypes 3 and 4, the main causes of chronic infection. The present findings provide insight concerning the advantage of combination therapy using drugs blocking different steps in the HEV life cycle (internalization and RNA replication) as a potential novel treatment strategy for chronic hepatitis E.https://www.mdpi.com/1999-4915/14/11/2440hepatitis E virusritonavirvirus internalizationribavirindrug combinationin vitro |
| spellingShingle | Putu Prathiwi Primadharsini Shigeo Nagashima Masaharu Takahashi Kazumoto Murata Hiroaki Okamoto Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin Viruses hepatitis E virus ritonavir virus internalization ribavirin drug combination in vitro |
| title | Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin |
| title_full | Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin |
| title_fullStr | Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin |
| title_full_unstemmed | Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin |
| title_short | Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin |
| title_sort | ritonavir blocks hepatitis e virus internalization and clears hepatitis e virus in vitro with ribavirin |
| topic | hepatitis E virus ritonavir virus internalization ribavirin drug combination in vitro |
| url | https://www.mdpi.com/1999-4915/14/11/2440 |
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