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Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2′,5′-oligoadenylate synthetase 1b
Abstract The interferon-inducible 2′,5′-oligoadenylate synthetase 1b (Oas1b) protein inhibits West Nile virus (WNV) infection by preventing viral RNA (vRNA) accumulation in infected cells. Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. T...
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Published in: | Virology (New York, N.Y.) N.Y.), 2010-03, Vol.399 (1), p.176-185 |
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creator | Mertens, Eva Kajaste-Rudnitski, Anna Torres, Shessy Funk, Anneke Frenkiel, Marie-Pascale Iteman, Isabelle Khromykh, Alexander A Desprès, Philippe |
description | Abstract The interferon-inducible 2′,5′-oligoadenylate synthetase 1b (Oas1b) protein inhibits West Nile virus (WNV) infection by preventing viral RNA (vRNA) accumulation in infected cells. Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. Two major amino acid substitutions were identified in this Oas1b-resistant WNV variant: NS3-S365G in the ATPase/helicase domain of NS3 and 2K-V9M in the C-terminal segment of NS4A. To assess their effect on antiviral activity of Oas1b, the NS3 and 2K mutations were engineered into an infectious WNV cDNA clone. The NS3 mutation alters requirement of ATP for ATPase activity and attenuates Oas1b-mediated suppression of vRNA accumulation. However, growth of NS3-mutant virus remains impaired in Oas1b-expressing cells. Only the 2K-V9M mutation efficiently rescued viral growth by promoting vRNA replication. Thus, WNV resistance to Oas1b antiviral action could be attributed to the 2K-V9M substitution with a potential role of NS3-S365G through rescue of vRNA accumulation. |
doi_str_mv | 10.1016/j.virol.2009.12.036 |
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Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. Two major amino acid substitutions were identified in this Oas1b-resistant WNV variant: NS3-S365G in the ATPase/helicase domain of NS3 and 2K-V9M in the C-terminal segment of NS4A. To assess their effect on antiviral activity of Oas1b, the NS3 and 2K mutations were engineered into an infectious WNV cDNA clone. The NS3 mutation alters requirement of ATP for ATPase activity and attenuates Oas1b-mediated suppression of vRNA accumulation. However, growth of NS3-mutant virus remains impaired in Oas1b-expressing cells. Only the 2K-V9M mutation efficiently rescued viral growth by promoting vRNA replication. Thus, WNV resistance to Oas1b antiviral action could be attributed to the 2K-V9M substitution with a potential role of NS3-S365G through rescue of vRNA accumulation.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1016/j.virol.2009.12.036</identifier><identifier>PMID: 20100623</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>2',5'-oligoadenylate synthetase ; 2',5'-Oligoadenylate Synthetase - pharmacology ; 2',5'-Oligoadenylate Synthetase - physiology ; 2′,5′-oligoadenylate synthetases ; adenosinetriphosphatase ; amino acid substitution ; Amino Acid Substitution - genetics ; Animals ; antiviral properties ; Disease Susceptibility ; DNA helicases ; DNA Helicases - metabolism ; DNA Helicases - physiology ; Flavivirus 2K peptide ; Flavivirus NS3 helicase ; Gene Expression Regulation, Viral ; Infectious Disease ; Innate immunity ; Mice ; nucleotidyltransferases ; Point Mutation - genetics ; RNA, Viral - genetics ; Viral evasion ; viral nonstructural proteins ; Virus Replication - physiology ; West Nile Fever - drug therapy ; West Nile Fever - genetics ; West Nile Fever - virology ; West Nile virus ; West Nile virus - genetics ; West Nile virus - pathogenicity ; West Nile virus - physiology</subject><ispartof>Virology (New York, N.Y.), 2010-03, Vol.399 (1), p.176-185</ispartof><rights>Elsevier Inc.</rights><rights>2009 Elsevier Inc.</rights><rights>Copyright 2009 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-ff58ed6af9da0a765802c7299bc403f55c820e437865fe346a9e45fda8d4baf93</citedby><cites>FETCH-LOGICAL-c469t-ff58ed6af9da0a765802c7299bc403f55c820e437865fe346a9e45fda8d4baf93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20100623$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mertens, Eva</creatorcontrib><creatorcontrib>Kajaste-Rudnitski, Anna</creatorcontrib><creatorcontrib>Torres, Shessy</creatorcontrib><creatorcontrib>Funk, Anneke</creatorcontrib><creatorcontrib>Frenkiel, Marie-Pascale</creatorcontrib><creatorcontrib>Iteman, Isabelle</creatorcontrib><creatorcontrib>Khromykh, Alexander A</creatorcontrib><creatorcontrib>Desprès, Philippe</creatorcontrib><title>Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2′,5′-oligoadenylate synthetase 1b</title><title>Virology (New York, N.Y.)</title><addtitle>Virology</addtitle><description>Abstract The interferon-inducible 2′,5′-oligoadenylate synthetase 1b (Oas1b) protein inhibits West Nile virus (WNV) infection by preventing viral RNA (vRNA) accumulation in infected cells. Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. Two major amino acid substitutions were identified in this Oas1b-resistant WNV variant: NS3-S365G in the ATPase/helicase domain of NS3 and 2K-V9M in the C-terminal segment of NS4A. To assess their effect on antiviral activity of Oas1b, the NS3 and 2K mutations were engineered into an infectious WNV cDNA clone. The NS3 mutation alters requirement of ATP for ATPase activity and attenuates Oas1b-mediated suppression of vRNA accumulation. However, growth of NS3-mutant virus remains impaired in Oas1b-expressing cells. Only the 2K-V9M mutation efficiently rescued viral growth by promoting vRNA replication. Thus, WNV resistance to Oas1b antiviral action could be attributed to the 2K-V9M substitution with a potential role of NS3-S365G through rescue of vRNA accumulation.</description><subject>2',5'-oligoadenylate synthetase</subject><subject>2',5'-Oligoadenylate Synthetase - pharmacology</subject><subject>2',5'-Oligoadenylate Synthetase - physiology</subject><subject>2′,5′-oligoadenylate synthetases</subject><subject>adenosinetriphosphatase</subject><subject>amino acid substitution</subject><subject>Amino Acid Substitution - genetics</subject><subject>Animals</subject><subject>antiviral properties</subject><subject>Disease Susceptibility</subject><subject>DNA helicases</subject><subject>DNA Helicases - metabolism</subject><subject>DNA Helicases - physiology</subject><subject>Flavivirus 2K peptide</subject><subject>Flavivirus NS3 helicase</subject><subject>Gene Expression Regulation, Viral</subject><subject>Infectious Disease</subject><subject>Innate immunity</subject><subject>Mice</subject><subject>nucleotidyltransferases</subject><subject>Point Mutation - genetics</subject><subject>RNA, Viral - genetics</subject><subject>Viral evasion</subject><subject>viral nonstructural proteins</subject><subject>Virus Replication - physiology</subject><subject>West Nile Fever - drug therapy</subject><subject>West Nile Fever - genetics</subject><subject>West Nile Fever - virology</subject><subject>West Nile virus</subject><subject>West Nile virus - genetics</subject><subject>West Nile virus - pathogenicity</subject><subject>West Nile virus - physiology</subject><issn>0042-6822</issn><issn>1096-0341</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNqFks1uEzEQx1cIREvhCZDANy5sGNu73t0DSKjiS1TlEApHy7FnWwdnHWwnUm68B2_BI_EkTJrCgUsvtqz5_efD_6mqxxxmHLh6sZxtfYphJgCGGRczkOpOdcxhUDXIht-tjgEaUateiKPqQc5LoHfXwf3qSAAHUEIeVz-_-GQCc1gwrfxkppKZn1i5QnY-l-wKg7cmIzOTY-IjW-O6eIcUN4WtU1zFguwr5sLOfUBGDW0yS5h9LmayxEVSFr-9LmJs8XFicWTi949fz1s66hj8ZTQOp10wlCrvJipd9hX54mF1bzQh46Ob-6S6ePvm8-n7-uzTuw-nr89q26ih1OPY9uiUGQdnwHSq7UHYTgzDwjYgx7a1vQBsZNerdkTZKDNg047O9K5ZkEqeVM8OeWmg7xsaRq98thiCmTBusu6UEB2Hpr-dlFINHIQiUh5Im2LOCUe9Tn5l0k5z0Hv79FJf26f39mkuNNlHqic3-TeLFbp_mr9-EfD0AIwmanOZfNYXc4pK4L2UxBDx8kAg_djWY9LZeiQvnE9oi3bR39LCq__0NviJliB8wx3mZdykiczQXGcS6Pl-x_YrRg0CcN7KP1fCzhY</recordid><startdate>20100330</startdate><enddate>20100330</enddate><creator>Mertens, Eva</creator><creator>Kajaste-Rudnitski, Anna</creator><creator>Torres, Shessy</creator><creator>Funk, Anneke</creator><creator>Frenkiel, Marie-Pascale</creator><creator>Iteman, Isabelle</creator><creator>Khromykh, Alexander A</creator><creator>Desprès, Philippe</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>7U9</scope><scope>F1W</scope><scope>H94</scope><scope>H95</scope><scope>L.G</scope></search><sort><creationdate>20100330</creationdate><title>Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2′,5′-oligoadenylate synthetase 1b</title><author>Mertens, Eva ; Kajaste-Rudnitski, Anna ; Torres, Shessy ; Funk, Anneke ; Frenkiel, Marie-Pascale ; Iteman, Isabelle ; Khromykh, Alexander A ; Desprès, Philippe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-ff58ed6af9da0a765802c7299bc403f55c820e437865fe346a9e45fda8d4baf93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>2',5'-oligoadenylate synthetase</topic><topic>2',5'-Oligoadenylate Synthetase - pharmacology</topic><topic>2',5'-Oligoadenylate Synthetase - physiology</topic><topic>2′,5′-oligoadenylate synthetases</topic><topic>adenosinetriphosphatase</topic><topic>amino acid substitution</topic><topic>Amino Acid Substitution - genetics</topic><topic>Animals</topic><topic>antiviral properties</topic><topic>Disease Susceptibility</topic><topic>DNA helicases</topic><topic>DNA Helicases - metabolism</topic><topic>DNA Helicases - physiology</topic><topic>Flavivirus 2K peptide</topic><topic>Flavivirus NS3 helicase</topic><topic>Gene Expression Regulation, Viral</topic><topic>Infectious Disease</topic><topic>Innate immunity</topic><topic>Mice</topic><topic>nucleotidyltransferases</topic><topic>Point Mutation - genetics</topic><topic>RNA, Viral - genetics</topic><topic>Viral evasion</topic><topic>viral nonstructural proteins</topic><topic>Virus Replication - physiology</topic><topic>West Nile Fever - drug therapy</topic><topic>West Nile Fever - genetics</topic><topic>West Nile Fever - virology</topic><topic>West Nile virus</topic><topic>West Nile virus - genetics</topic><topic>West Nile virus - pathogenicity</topic><topic>West Nile virus - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mertens, Eva</creatorcontrib><creatorcontrib>Kajaste-Rudnitski, Anna</creatorcontrib><creatorcontrib>Torres, Shessy</creatorcontrib><creatorcontrib>Funk, Anneke</creatorcontrib><creatorcontrib>Frenkiel, Marie-Pascale</creatorcontrib><creatorcontrib>Iteman, Isabelle</creatorcontrib><creatorcontrib>Khromykh, Alexander A</creatorcontrib><creatorcontrib>Desprès, Philippe</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><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>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><jtitle>Virology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mertens, Eva</au><au>Kajaste-Rudnitski, Anna</au><au>Torres, Shessy</au><au>Funk, Anneke</au><au>Frenkiel, Marie-Pascale</au><au>Iteman, Isabelle</au><au>Khromykh, Alexander A</au><au>Desprès, Philippe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2′,5′-oligoadenylate synthetase 1b</atitle><jtitle>Virology (New York, N.Y.)</jtitle><addtitle>Virology</addtitle><date>2010-03-30</date><risdate>2010</risdate><volume>399</volume><issue>1</issue><spage>176</spage><epage>185</epage><pages>176-185</pages><issn>0042-6822</issn><eissn>1096-0341</eissn><abstract>Abstract The interferon-inducible 2′,5′-oligoadenylate synthetase 1b (Oas1b) protein inhibits West Nile virus (WNV) infection by preventing viral RNA (vRNA) accumulation in infected cells. Serial passage of WNV in Oas1b-expressing mouse cells selected a virus variant with improved growth capacity. Two major amino acid substitutions were identified in this Oas1b-resistant WNV variant: NS3-S365G in the ATPase/helicase domain of NS3 and 2K-V9M in the C-terminal segment of NS4A. To assess their effect on antiviral activity of Oas1b, the NS3 and 2K mutations were engineered into an infectious WNV cDNA clone. The NS3 mutation alters requirement of ATP for ATPase activity and attenuates Oas1b-mediated suppression of vRNA accumulation. However, growth of NS3-mutant virus remains impaired in Oas1b-expressing cells. Only the 2K-V9M mutation efficiently rescued viral growth by promoting vRNA replication. Thus, WNV resistance to Oas1b antiviral action could be attributed to the 2K-V9M substitution with a potential role of NS3-S365G through rescue of vRNA accumulation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20100623</pmid><doi>10.1016/j.virol.2009.12.036</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 2',5'-oligoadenylate synthetase 2',5'-Oligoadenylate Synthetase - pharmacology 2',5'-Oligoadenylate Synthetase - physiology 2′,5′-oligoadenylate synthetases adenosinetriphosphatase amino acid substitution Amino Acid Substitution - genetics Animals antiviral properties Disease Susceptibility DNA helicases DNA Helicases - metabolism DNA Helicases - physiology Flavivirus 2K peptide Flavivirus NS3 helicase Gene Expression Regulation, Viral Infectious Disease Innate immunity Mice nucleotidyltransferases Point Mutation - genetics RNA, Viral - genetics Viral evasion viral nonstructural proteins Virus Replication - physiology West Nile Fever - drug therapy West Nile Fever - genetics West Nile Fever - virology West Nile virus West Nile virus - genetics West Nile virus - pathogenicity West Nile virus - physiology |
title | Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2′,5′-oligoadenylate synthetase 1b |
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