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A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir
Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the...
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| Published in: | Journal of general virology 2021-01, Vol.102 (1) |
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| container_issue | 1 |
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| container_title | Journal of general virology |
| container_volume | 102 |
| creator | Fernandes Campos, Guilherme Rodrigues Ward, Joseph Chen, Shucheng Bittar, Cintia Vilela Rodrigues, João Paulo Martinelli, Ana de Lourdes Candolo Souza, Fernanda Fernandes Pereira, Leonardo Régis Leira Rahal, Paula Harris, Mark |
| description | Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs. |
| doi_str_mv | 10.1099/jgv.0.001496 |
| format | article |
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To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.</description><identifier>ISSN: 0022-1317</identifier><identifier>EISSN: 1465-2099</identifier><identifier>DOI: 10.1099/jgv.0.001496</identifier><identifier>PMID: 33141008</identifier><language>eng</language><publisher>England: Microbiology Society</publisher><subject>Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Brazil ; Carbamates - pharmacology ; Carbamates - therapeutic use ; Cell Line, Tumor ; Cohort Studies ; Drug Resistance, Viral - drug effects ; Drug Resistance, Viral - genetics ; Drug Therapy, Combination ; Genotype ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepacivirus - physiology ; Hepatitis C - drug therapy ; Hepatitis C - virology ; Humans ; Imidazoles - pharmacology ; Imidazoles - therapeutic use ; Mutation ; Pyrrolidines - pharmacology ; Pyrrolidines - therapeutic use ; Recurrence ; Sofosbuvir - pharmacology ; Sofosbuvir - therapeutic use ; Valine - analogs & derivatives ; Valine - pharmacology ; Valine - therapeutic use ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - genetics ; Virus Replication - genetics</subject><ispartof>Journal of general virology, 2021-01, Vol.102 (1)</ispartof><rights>2021 The Authors 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-204943acdae1831cb7b23eb69a85b73be0b2a6ac82c2e85dd26e75129f1dbe4c3</citedby><cites>FETCH-LOGICAL-c384t-204943acdae1831cb7b23eb69a85b73be0b2a6ac82c2e85dd26e75129f1dbe4c3</cites><orcidid>0000-0001-9041-1986 ; 0000-0002-5785-1418 ; 0000-0003-1118-8486 ; 0000-0001-9867-393X ; 0000-0002-2048-4589 ; 0000-0002-9821-1003 ; 0000-0002-1713-9039</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33141008$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fernandes Campos, Guilherme Rodrigues</creatorcontrib><creatorcontrib>Ward, Joseph</creatorcontrib><creatorcontrib>Chen, Shucheng</creatorcontrib><creatorcontrib>Bittar, Cintia</creatorcontrib><creatorcontrib>Vilela Rodrigues, João Paulo</creatorcontrib><creatorcontrib>Martinelli, Ana de Lourdes Candolo</creatorcontrib><creatorcontrib>Souza, Fernanda Fernandes</creatorcontrib><creatorcontrib>Pereira, Leonardo Régis Leira</creatorcontrib><creatorcontrib>Rahal, Paula</creatorcontrib><creatorcontrib>Harris, Mark</creatorcontrib><title>A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir</title><title>Journal of general virology</title><addtitle>J Gen Virol</addtitle><description>Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. 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Ward, Joseph ; Chen, Shucheng ; Bittar, Cintia ; Vilela Rodrigues, João Paulo ; Martinelli, Ana de Lourdes Candolo ; Souza, Fernanda Fernandes ; Pereira, Leonardo Régis Leira ; Rahal, Paula ; Harris, Mark</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-204943acdae1831cb7b23eb69a85b73be0b2a6ac82c2e85dd26e75129f1dbe4c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Brazil</topic><topic>Carbamates - pharmacology</topic><topic>Carbamates - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Cohort Studies</topic><topic>Drug Resistance, Viral - drug effects</topic><topic>Drug Resistance, Viral - genetics</topic><topic>Drug Therapy, Combination</topic><topic>Genotype</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - genetics</topic><topic>Hepacivirus - physiology</topic><topic>Hepatitis C - drug therapy</topic><topic>Hepatitis C - virology</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Imidazoles - therapeutic use</topic><topic>Mutation</topic><topic>Pyrrolidines - pharmacology</topic><topic>Pyrrolidines - therapeutic use</topic><topic>Recurrence</topic><topic>Sofosbuvir - pharmacology</topic><topic>Sofosbuvir - therapeutic use</topic><topic>Valine - analogs & derivatives</topic><topic>Valine - pharmacology</topic><topic>Valine - therapeutic use</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - genetics</topic><topic>Virus Replication - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fernandes Campos, Guilherme Rodrigues</creatorcontrib><creatorcontrib>Ward, Joseph</creatorcontrib><creatorcontrib>Chen, Shucheng</creatorcontrib><creatorcontrib>Bittar, Cintia</creatorcontrib><creatorcontrib>Vilela Rodrigues, João Paulo</creatorcontrib><creatorcontrib>Martinelli, Ana de Lourdes Candolo</creatorcontrib><creatorcontrib>Souza, Fernanda Fernandes</creatorcontrib><creatorcontrib>Pereira, Leonardo Régis Leira</creatorcontrib><creatorcontrib>Rahal, Paula</creatorcontrib><creatorcontrib>Harris, Mark</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of general virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fernandes Campos, Guilherme Rodrigues</au><au>Ward, Joseph</au><au>Chen, Shucheng</au><au>Bittar, Cintia</au><au>Vilela Rodrigues, João Paulo</au><au>Martinelli, Ana de Lourdes Candolo</au><au>Souza, Fernanda Fernandes</au><au>Pereira, Leonardo Régis Leira</au><au>Rahal, Paula</au><au>Harris, Mark</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir</atitle><jtitle>Journal of general virology</jtitle><addtitle>J Gen Virol</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>102</volume><issue>1</issue><issn>0022-1317</issn><eissn>1465-2099</eissn><abstract>Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. 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| subjects | Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Brazil Carbamates - pharmacology Carbamates - therapeutic use Cell Line, Tumor Cohort Studies Drug Resistance, Viral - drug effects Drug Resistance, Viral - genetics Drug Therapy, Combination Genotype Hepacivirus - drug effects Hepacivirus - genetics Hepacivirus - physiology Hepatitis C - drug therapy Hepatitis C - virology Humans Imidazoles - pharmacology Imidazoles - therapeutic use Mutation Pyrrolidines - pharmacology Pyrrolidines - therapeutic use Recurrence Sofosbuvir - pharmacology Sofosbuvir - therapeutic use Valine - analogs & derivatives Valine - pharmacology Valine - therapeutic use Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - genetics Virus Replication - genetics |
| title | A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir |
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