Antiviral Activity of 3(2H)- and 6-Chloro-3(2H)-Isoflavenes against Highly Diverged, Neurovirulent Vaccine-Derived, Type2 Poliovirus Sewage Isolates 英文参考文献.docVIP

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Antiviral Activity of 3(2H)- and 6-Chloro-3(2H)-Isoflavenes against Highly Diverged, Neurovirulent Vaccine-Derived, Type2 Poliovirus Sewage Isolates 英文参考文献.doc

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Antiviral Activity of 3(2H)- and 6-Chloro-3(2H)-Isoflavenes against Highly Diverged, Neurovirulent Vaccine-Derived, Type2 Poliovirus Sewage Isolates 英文参考文献

AntiviralActivityof3(2H)-and6-Chloro-3(2H)- IsoflavenesagainstHighlyDiverged,Neurovirulent Vaccine-Derived,Type2PoliovirusSewageIsolates LesterM.Shulman1,2*,DanitSofer1,YossiManor1,EllaMendelson1,2,JeanBalanant3,4,AnnaLaura Salvati5,FrancisDelpeyroux3,4,LuciaFiore5 1Central Virology Laboratory, Public Health Services Israel Ministry of Health, Chaim Sheba Medical Center, Tel Hashomer, Israel, 2Department of Epidemiology and PreventiveMedicine,SacklerFacultyofMedicine,UniversityofTelAviv,RamatGan,Israel,3BiologyofEntericViruses,InstitutPasteur,Paris,France,4InstitutNationalde laSante′ etdelaRechercheMe′dicale(INSERM)U994,Paris,France,5NationalCenterforImmunobiologicalsResearchandEvaluation(CRIVIB),IstitutoSuperiorediSanita`, VialeReginaElena,Rome,Italy Abstract Background: Substituted flavanoids interfere with uncoating of Enteroviruses including Sabin-2 polio vaccine strains. However flavanoid resistant and dependent, type-2 polio vaccine strains (minimally-diverged), emerged during in vitro infections. Between 1998–2009, highly-diverged (8 to .15%) type-2, aVDPV2s, from two unrelated persistent infections wereperiodicallyisolatedfromIsraelisewage. Aim:TodeterminewhetherhighlyevolvedaVDPV2sderivedfrompersistentinfectionsretainedsensitivitytoisoflavenes. Methods:Sabin-2andtenaVDPV2isolatesfromtwoindependentIsraelisourcesweretiteredonHEp2Ccellsinthepresence andabsenceof3(2H)-Isoflaveneand6-chloro-3(2H)-Isoflavene.NeurovirulenceofnineaVDPV2swasmeasuredinPVR-Tg-21 transgenicmice.Differenceswererelatedtouniqueaminoacidsubstitutionswithincapsidproteins. PrincipalFindings:ThepresenceofeitherflavanoidinhibitedviraltitersofSabin-2andnineoftenaVDPV2sbyonetotwo log10. The tenth aVDPV2, which had unique amino acid substitution distant from the isoflavene-binding pocket but clusteredatthethree-andfive-foldaxiesofsymmetrybetweencapsomeres,wasunaffectedbybothflavanoids.Genotypic neurovirulence attenuation sites in the 59UTR and VP1 reverted in all aVDPV2s and all reacquired a fu