Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs
Aims Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has...
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| Veröffentlicht in: | Hepatology research 2019-11, Vol.49 (11), p.1275-1285 |
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| creator | Suda, Goki Kimura, Megumi Shigesawa, Taku Suzuki, Kazuharu Nakamura, Akihisa Ohara, Masatsugu Kawagishi, Naoki Nakai, Masato Sho, Takuya Maehara, Osamu Shimazaki, Tomoe Morikawa, Kenichi Natsuizaka, Mitsuteru Ogawa, Koji Sakamoto, Naoya |
| description | Aims
Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non‐structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy.
Methods
We utilized HCV‐2b/2a (JFH‐1) chimeric virus (genotype 2a), which replicates more robustly than JFH‐1. We constructed various genotype 2a JFH‐1‐based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti‐HCV reagents.
Results
Genotype 2a‐based HCV with NS5A–P32 deletion could not replicate even in long‐term cultures. Genotype 2a‐based HCV with NS5A‐F28S/M31I showed significantly higher replication ability than the wild‐type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir ( |
| doi_str_mv | 10.1111/hepr.13401 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2251101381</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2251101381</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4471-d5d7c8c04c48be46ca2d2327911e0ddefe878113e48037978f94de4be7e9da143</originalsourceid><addsrcrecordid>eNp9kdFqFDEUhoMotlZvfAAJeCPC1JwkO5m5lGW1hYIiCt6FbHKmpszOjEmmZe98BMEX8Fl8lD5Jz3arFwrmJuHk4zsn-Rl7CuIYaL36glM6BqUF3GOH0BhZCaU_36ezauqqVro-YI9yvhACjJD6ITtQIGvQqj1kP1Zdh75kPnY8YY65uMHj9bfvLufRR1cw8EuXohuIiQM_x2Es2wm5_PWT-roSS8x8yS9jmkky7A6uJ9XUR0-3VHFD4HnOHqcS17GPZcvLSNUS_xWENJ_nx-xB5_qMT-72I_bpzerj8qQ6e_f2dPn6rPJaG6jCIhjfeKG9btaoa-9kkEqaFgBFCNhhYxoAhboRyrSm6VodUK_RYBscPf-Ivdh7pzR-nTEXu4k0Zt-7Acc5WykXAII-EQh9_hd6Mc5poOkstZRts2hFTdTLPeXTmHPCzk4pblzaWhB2F5XdRWVvoyL42Z1yXm8w_EF_Z0MA7IGr2OP2Pyp7snr_YS-9AeLZowE</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2322985906</pqid></control><display><type>article</type><title>Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs</title><source>Wiley Online Library Journals Frontfile Complete</source><creator>Suda, Goki ; Kimura, Megumi ; Shigesawa, Taku ; Suzuki, Kazuharu ; Nakamura, Akihisa ; Ohara, Masatsugu ; Kawagishi, Naoki ; Nakai, Masato ; Sho, Takuya ; Maehara, Osamu ; Shimazaki, Tomoe ; Morikawa, Kenichi ; Natsuizaka, Mitsuteru ; Ogawa, Koji ; Sakamoto, Naoya</creator><creatorcontrib>Suda, Goki ; Kimura, Megumi ; Shigesawa, Taku ; Suzuki, Kazuharu ; Nakamura, Akihisa ; Ohara, Masatsugu ; Kawagishi, Naoki ; Nakai, Masato ; Sho, Takuya ; Maehara, Osamu ; Shimazaki, Tomoe ; Morikawa, Kenichi ; Natsuizaka, Mitsuteru ; Ogawa, Koji ; Sakamoto, Naoya</creatorcontrib><description>Aims
Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non‐structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy.
Methods
We utilized HCV‐2b/2a (JFH‐1) chimeric virus (genotype 2a), which replicates more robustly than JFH‐1. We constructed various genotype 2a JFH‐1‐based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti‐HCV reagents.
Results
Genotype 2a‐based HCV with NS5A–P32 deletion could not replicate even in long‐term cultures. Genotype 2a‐based HCV with NS5A‐F28S/M31I showed significantly higher replication ability than the wild‐type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000–10 000 fold‐resistance compared with the wild‐type strain). However, genotype 2a‐based HCV with NA5A‐F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon‐α, and ribavirin. Genotype 2a‐based HCV with NS5B‐S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control.
Conclusions
When undertaking retreatment for genotype 2a HCV‐infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti‐HCV drugs.</description><identifier>ISSN: 1386-6346</identifier><identifier>EISSN: 1872-034X</identifier><identifier>DOI: 10.1111/hepr.13401</identifier><identifier>PMID: 31261439</identifier><language>eng</language><publisher>Netherlands: Wiley Subscription Services, Inc</publisher><subject>Antiviral agents ; Cell culture ; Clonal deletion ; Disease resistance ; Drug development ; Gene deletion ; Genotype & phenotype ; genotype 2 ; Genotypes ; Hepatitis C ; hepatitis C virus ; Interferon ; NS5A F28S/M31I ; NS5B S282 T ; Proteinase inhibitors ; Replication ; resistant‐associated variant ; Ribavirin</subject><ispartof>Hepatology research, 2019-11, Vol.49 (11), p.1275-1285</ispartof><rights>2019 The Japan Society of Hepatology</rights><rights>2019 The Japan Society of Hepatology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4471-d5d7c8c04c48be46ca2d2327911e0ddefe878113e48037978f94de4be7e9da143</citedby><cites>FETCH-LOGICAL-c4471-d5d7c8c04c48be46ca2d2327911e0ddefe878113e48037978f94de4be7e9da143</cites><orcidid>0000-0002-3891-5113 ; 0000-0003-0098-9106 ; 0000-0002-2953-6242</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fhepr.13401$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fhepr.13401$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31261439$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Suda, Goki</creatorcontrib><creatorcontrib>Kimura, Megumi</creatorcontrib><creatorcontrib>Shigesawa, Taku</creatorcontrib><creatorcontrib>Suzuki, Kazuharu</creatorcontrib><creatorcontrib>Nakamura, Akihisa</creatorcontrib><creatorcontrib>Ohara, Masatsugu</creatorcontrib><creatorcontrib>Kawagishi, Naoki</creatorcontrib><creatorcontrib>Nakai, Masato</creatorcontrib><creatorcontrib>Sho, Takuya</creatorcontrib><creatorcontrib>Maehara, Osamu</creatorcontrib><creatorcontrib>Shimazaki, Tomoe</creatorcontrib><creatorcontrib>Morikawa, Kenichi</creatorcontrib><creatorcontrib>Natsuizaka, Mitsuteru</creatorcontrib><creatorcontrib>Ogawa, Koji</creatorcontrib><creatorcontrib>Sakamoto, Naoya</creatorcontrib><title>Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs</title><title>Hepatology research</title><addtitle>Hepatol Res</addtitle><description>Aims
Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non‐structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy.
Methods
We utilized HCV‐2b/2a (JFH‐1) chimeric virus (genotype 2a), which replicates more robustly than JFH‐1. We constructed various genotype 2a JFH‐1‐based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti‐HCV reagents.
Results
Genotype 2a‐based HCV with NS5A–P32 deletion could not replicate even in long‐term cultures. Genotype 2a‐based HCV with NS5A‐F28S/M31I showed significantly higher replication ability than the wild‐type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000–10 000 fold‐resistance compared with the wild‐type strain). However, genotype 2a‐based HCV with NA5A‐F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon‐α, and ribavirin. Genotype 2a‐based HCV with NS5B‐S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control.
Conclusions
When undertaking retreatment for genotype 2a HCV‐infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti‐HCV drugs.</description><subject>Antiviral agents</subject><subject>Cell culture</subject><subject>Clonal deletion</subject><subject>Disease resistance</subject><subject>Drug development</subject><subject>Gene deletion</subject><subject>Genotype & phenotype</subject><subject>genotype 2</subject><subject>Genotypes</subject><subject>Hepatitis C</subject><subject>hepatitis C virus</subject><subject>Interferon</subject><subject>NS5A F28S/M31I</subject><subject>NS5B S282 T</subject><subject>Proteinase inhibitors</subject><subject>Replication</subject><subject>resistant‐associated variant</subject><subject>Ribavirin</subject><issn>1386-6346</issn><issn>1872-034X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kdFqFDEUhoMotlZvfAAJeCPC1JwkO5m5lGW1hYIiCt6FbHKmpszOjEmmZe98BMEX8Fl8lD5Jz3arFwrmJuHk4zsn-Rl7CuIYaL36glM6BqUF3GOH0BhZCaU_36ezauqqVro-YI9yvhACjJD6ITtQIGvQqj1kP1Zdh75kPnY8YY65uMHj9bfvLufRR1cw8EuXohuIiQM_x2Es2wm5_PWT-roSS8x8yS9jmkky7A6uJ9XUR0-3VHFD4HnOHqcS17GPZcvLSNUS_xWENJ_nx-xB5_qMT-72I_bpzerj8qQ6e_f2dPn6rPJaG6jCIhjfeKG9btaoa-9kkEqaFgBFCNhhYxoAhboRyrSm6VodUK_RYBscPf-Ivdh7pzR-nTEXu4k0Zt-7Acc5WykXAII-EQh9_hd6Mc5poOkstZRts2hFTdTLPeXTmHPCzk4pblzaWhB2F5XdRWVvoyL42Z1yXm8w_EF_Z0MA7IGr2OP2Pyp7snr_YS-9AeLZowE</recordid><startdate>201911</startdate><enddate>201911</enddate><creator>Suda, Goki</creator><creator>Kimura, Megumi</creator><creator>Shigesawa, Taku</creator><creator>Suzuki, Kazuharu</creator><creator>Nakamura, Akihisa</creator><creator>Ohara, Masatsugu</creator><creator>Kawagishi, Naoki</creator><creator>Nakai, Masato</creator><creator>Sho, Takuya</creator><creator>Maehara, Osamu</creator><creator>Shimazaki, Tomoe</creator><creator>Morikawa, Kenichi</creator><creator>Natsuizaka, Mitsuteru</creator><creator>Ogawa, Koji</creator><creator>Sakamoto, Naoya</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3891-5113</orcidid><orcidid>https://orcid.org/0000-0003-0098-9106</orcidid><orcidid>https://orcid.org/0000-0002-2953-6242</orcidid></search><sort><creationdate>201911</creationdate><title>Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs</title><author>Suda, Goki ; Kimura, Megumi ; Shigesawa, Taku ; Suzuki, Kazuharu ; Nakamura, Akihisa ; Ohara, Masatsugu ; Kawagishi, Naoki ; Nakai, Masato ; Sho, Takuya ; Maehara, Osamu ; Shimazaki, Tomoe ; Morikawa, Kenichi ; Natsuizaka, Mitsuteru ; Ogawa, Koji ; Sakamoto, Naoya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4471-d5d7c8c04c48be46ca2d2327911e0ddefe878113e48037978f94de4be7e9da143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Antiviral agents</topic><topic>Cell culture</topic><topic>Clonal deletion</topic><topic>Disease resistance</topic><topic>Drug development</topic><topic>Gene deletion</topic><topic>Genotype & phenotype</topic><topic>genotype 2</topic><topic>Genotypes</topic><topic>Hepatitis C</topic><topic>hepatitis C virus</topic><topic>Interferon</topic><topic>NS5A F28S/M31I</topic><topic>NS5B S282 T</topic><topic>Proteinase inhibitors</topic><topic>Replication</topic><topic>resistant‐associated variant</topic><topic>Ribavirin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Suda, Goki</creatorcontrib><creatorcontrib>Kimura, Megumi</creatorcontrib><creatorcontrib>Shigesawa, Taku</creatorcontrib><creatorcontrib>Suzuki, Kazuharu</creatorcontrib><creatorcontrib>Nakamura, Akihisa</creatorcontrib><creatorcontrib>Ohara, Masatsugu</creatorcontrib><creatorcontrib>Kawagishi, Naoki</creatorcontrib><creatorcontrib>Nakai, Masato</creatorcontrib><creatorcontrib>Sho, Takuya</creatorcontrib><creatorcontrib>Maehara, Osamu</creatorcontrib><creatorcontrib>Shimazaki, Tomoe</creatorcontrib><creatorcontrib>Morikawa, Kenichi</creatorcontrib><creatorcontrib>Natsuizaka, Mitsuteru</creatorcontrib><creatorcontrib>Ogawa, Koji</creatorcontrib><creatorcontrib>Sakamoto, Naoya</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Suda, Goki</au><au>Kimura, Megumi</au><au>Shigesawa, Taku</au><au>Suzuki, Kazuharu</au><au>Nakamura, Akihisa</au><au>Ohara, Masatsugu</au><au>Kawagishi, Naoki</au><au>Nakai, Masato</au><au>Sho, Takuya</au><au>Maehara, Osamu</au><au>Shimazaki, Tomoe</au><au>Morikawa, Kenichi</au><au>Natsuizaka, Mitsuteru</au><au>Ogawa, Koji</au><au>Sakamoto, Naoya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs</atitle><jtitle>Hepatology research</jtitle><addtitle>Hepatol Res</addtitle><date>2019-11</date><risdate>2019</risdate><volume>49</volume><issue>11</issue><spage>1275</spage><epage>1285</epage><pages>1275-1285</pages><issn>1386-6346</issn><eissn>1872-034X</eissn><abstract>Aims
Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non‐structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy.
Methods
We utilized HCV‐2b/2a (JFH‐1) chimeric virus (genotype 2a), which replicates more robustly than JFH‐1. We constructed various genotype 2a JFH‐1‐based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti‐HCV reagents.
Results
Genotype 2a‐based HCV with NS5A–P32 deletion could not replicate even in long‐term cultures. Genotype 2a‐based HCV with NS5A‐F28S/M31I showed significantly higher replication ability than the wild‐type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000–10 000 fold‐resistance compared with the wild‐type strain). However, genotype 2a‐based HCV with NA5A‐F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon‐α, and ribavirin. Genotype 2a‐based HCV with NS5B‐S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control.
Conclusions
When undertaking retreatment for genotype 2a HCV‐infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti‐HCV drugs.</abstract><cop>Netherlands</cop><pub>Wiley Subscription Services, Inc</pub><pmid>31261439</pmid><doi>10.1111/hepr.13401</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-3891-5113</orcidid><orcidid>https://orcid.org/0000-0003-0098-9106</orcidid><orcidid>https://orcid.org/0000-0002-2953-6242</orcidid></addata></record> |
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| ispartof | Hepatology research, 2019-11, Vol.49 (11), p.1275-1285 |
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| source | Wiley Online Library Journals Frontfile Complete |
| subjects | Antiviral agents Cell culture Clonal deletion Disease resistance Drug development Gene deletion Genotype & phenotype genotype 2 Genotypes Hepatitis C hepatitis C virus Interferon NS5A F28S/M31I NS5B S282 T Proteinase inhibitors Replication resistant‐associated variant Ribavirin |
| title | Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs |
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