RNA病毒的变异与消失.docx
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RNA病毒的变异与消失.docx
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RNA病毒的变异与消失
VirusResearch107(2005)129–139
QuasispeciesdynamicsandRNAvirusextinction
EstebanDomingoa,b,c,∗,CristinaEscarm´sa,EsterL´zarob,SusannaC.Manrubiabıa
a
CentrodeBiolog´aMolecular“SeveroOchoa”(CSIC-UAM),ConsejoSuperiordeInvestigacionesCientificas,ı
UniversidadAut´nomadeMadrid,Cantoblanco,28049Madrid,Spaino
bCentrodeAstrobiolog´a(CSIC-INTA),CarreteradeAjalvir,km4,28850Torrej´ndeArdoz,Madrid,Spainıo
cCentrodeInvestigaci´nenSanidadAnimal(INIA),Valdeolmos,28130Madrid,Spaino
Availableonline8December2004
Abstract
Theextinctionoffoot-and-mouthdiseasevirus(FMDV)isstronglyinfluencedbymutationrates,typesofmutations,relativeviralfitness
andviruspopulationregimensduringinfection.Herewereviewexperimentalresultsandtheoreticalmodelsthatdescribeacontrastbetween
theeffectiveextinctionofFMDVsubjectedtoincreasedmutagenesis,andtheremarkableresistancetoextinctionofthesameandrelated
FMDVclonessubjectedtoserialbottleneckevents.Theresultssuggestprocedurestomasterkeyparameterstodevelopeffectiveantiviral
strategiesbasedonvirusentryintoerrorcatastrophe.
©2004ElsevierB.V.Allrightsreserved.
Keywords:
Foot-and-mouthdiseasevirus;5-Fluorouracil;5-Azacytidine;Mutation
1.Introduction
Criticalforatherapeuticapplicationoferrorcatastrophe
asanantiviralstrategyistounderstandthemainfactors(in-
trinsictothevirusaswellasthoserelatedtopopulationdy-
namics)thatmaycontributetolossofinfectivity.Thishas
provenacomplexissueandtheexperimentscarriedoutsofar
haveraisedmorequestionsthanprovidedanswers.Herewe
reviewstudiescarriedoutoverthelastdecadewiththeimpor-
tantanimalpathogenfoot-and-mouthdiseasevirus(FMDV)
aimedatunderstandinghowhighmutationratesandqua-
sispeciesdynamics(asopposedtolowmutationratesand
anon-quasispeciesdynamics)affectedtheaccumulationof
mutations,fitnessvariations,andvirussurvival.Themain
pointofthisarticleistocomparetheremarkablecapacity
todriveFMDVintoerrorcatastrophewhentheeffectsof
threecriticalparameters(mutationrates,viralfitness,andvi-
ralload)areunderstoodandcontrolled,withtheresistance
toextinctiondespiteaccumulationofmutationsuponsub-
jectingFMDVtorepeatedbottleneckevents(experimentally
realizedasplaque-to-plaquetransfers).Theseverydiffer-
entresponsesregardingsurvivalmayshedlightonstrate-
gieswhosegoalistheeliminationofvirusduringinfectious
processesinvivo.
AsrecentintroductionstoFMDVthereaderisreferredto
thevolumesbyRowlands(2003)andSobrinoandDomingo
(2004).Forclarity,Table1includesaglossaryofconcepts
andtermsusedinthisarticleandintheliteratureonquasis-
peciesanderrorcatastrophe.
2.ExtinctionofFMDVbyenhancedmutagenesis
Followingpioneerworkontheadverseeffectsofchemical
mutagenesisontheinfectivityofpoliovirusandvesicular
stomatitisvirus(VSV)byHollandetal.(1990)andLeeet
al.(1997),ourgroupsettostudytheeffectofthemutagenic
baseanalog5-fluorouracil(FU)andthenucleosideanalog
5-azacytidine(AZT)ontheinfectivityandmutantspectrum
complexityofFMDV(Parienteetal.,2001,2003;Sierraet
al.,2000).Theseexperiments,andtheeffectofribavirinon
persistentFMDVinfections(Airaksinenetal.,2003;dela
Torreetal.,1987),arereviewedindetailby(Parienteetal.,
2005).Hereweextractthemainconclusionsonlytoserve
∗
Correspondingauthor.Tel.:
+34914978485;fax:
+34914974799.
E-mailaddress:
edomingo@cbm.uam.es(E.Domingo).
0168-1702/$–seefrontmatter©2004ElsevierB.V.Allrightsreserved.
doi:
10.1016/j.virusres.2004.11.003
130
E.Domingoetal./VirusResearch107(2005)129–139
Table1
Glossaryofsometermsfrequentlyusedintheliteratureofquasispeciesanderrorcatastrophe
Complexityofthemutantspectrum
Ameasureofthenucleotidesequencedifferencesamongcomponentsofamutantspectrum:
itisgenerallygiven
bythemutationfrequencyandShannonentropy.Complexityhasothermeaningsinscience,includingsizeof
genomes,usedalsointhetext
Thesequenceresultingfromtakingforeachpositionthemostfrequentresidue(nucleotideoraminoacid)foundat
thecorrespondingpositioninthehomologoussetofalignedsequences:
theconsensussequencemaynotexist
physicallyinthemutantspectrum
Acriticalerrorrateabovewhichtheinformationencodedbyageneticsystemcannotbemaintained:
violationof
theerrorthresholdresultsinthesystementeringerrorcatastrophe.Theerrorthresholdrelationshipisgivenby
νmax ¯maintainedduringreplication,σoisthesuperiorityofthemastersequencerelativetothemutantspectrum,andqis theaveragecopyingfidelity(theaverageerrorrateis(1−q))¯ Aparameterthatquantifiestheadaptationofanorganismoravirustoagivenenvironment: itisnecessarilya relativevalue.Foravirus,relativefitnessmeasuresitsabilitytoproduceinfectiousprogenyrelativetoareference viralclone,inadefinedenvironment.Epidemiologicalfitnessdescribesinsemi-quantitativeways(samplingof definitorygenomicsequencesversusthoseofcompetitors)therelativecapacityofavirustobecomedominantin thefieldduring(orasaresultof)epidemicoutbreaks Thedominantgenomicnucleotidesequenceinaquasispecies: itgenerallydepictsaselectiveadvantageoverthe othercomponentsofthequasispecies.Itmayormaynotcoincidewiththeconsensussequence.Themaster sequencemaychangeastheenvironmentismodified Theensembleofmutantgenomesthatcomposeaquasispecies Theproportionofmutantsinapopulationofgenomes: itmaybecalculatedforanentiresequenceofforaspecific siteofagenome(suchasinthefrequencyofmonoclonalantibody-escapemutants) Thefrequencyofoccurrenceofamutationaleventduringgenomereplication: intheliteratureofpopulation genetics,mutationrateisoftenusedtomeantherateoffixation(oraccumulation)ofmutations,orrateofevolution Thenumberofindividualsinapopulation: forviruses,thetermreferstothenumberofinfectiousgenomespresent inacell,tissue,organororganismthatatanygiventimeareeitherreplicatingorcanpotentiallyreplicate.The numberofgenomesquantifiedinaninfectedhostisalsotermedtheviralload.Notallviralgenomesareinfectious (seeSpecificinfectivity) Amutagenizedviralpopulationthatprecedestheonefromwhichnoinfectivitycanberescued: Preextinction RNAistheRNAextractedformapreextinctionpopulation Aweighteddistributionofmutantscenteredaroundonemastersequence: initsinitialmathematicalformulation,a quasispecieswasasteadystatedistributionofinfinitesizeinequilibrium.Mathematicalextensionstofinite populationundernon-equilibriumconditionshavebeendeveloped.Virologistsuseanextendeddefinitionof quasispeciesmeaning“dynamicdistributionsofnon-identicalbutcloselyrelatedmutantandrecombinantviral genomessubjectedtoacontinuousprocessofgeneticvariation,competitionandselection,andwhichactasaunit ofselection” Thefrequencyofmutationsthatbecomedominantinagenomeperunittime: foravirusitmaybecalculatedfor sequentialgenomesinaninfectedhostofforviralgenomessampledatdifferenttimesfromdifferentinfected hosts.Forvirusesthisrateisgenerallynotconstant.Theassumptionofa“molecularclock”isnotrealisticfor RNAviruses Atheoreticalrepresentationofallpossiblevariantsofagenomicsequence: forasinglestrandedRNAvirusof 10,000residues(usingfourtypesofnucleotides)thetotalsequencespaceis410,000! Viralgenomesoccupytiny portionsoftheirtheoreticalsequencespace Theproportionofdifferentnucleotidesequencesinamutantspectrum(avalueof1meanseachsequenceis uniqueinthedistribution;avalueof0meansthatallsequencesareidentical) Theproportionofinfectiousparticles(orinfectiousviralnucleicacid)inaviral(orviralgenome)population: the transitionintoerrorcatastropheisgenerallyprecededbydecreasesinspecificinfectivity Thenumberofinfectious(activelyreplicatingorpotentiallyreplicating)particlesinaviralpopulation Consensus(oraverage)sequence Errorthreshold Fitness Mastersequence Mutantspectrum Mutationfrequency Mutationrate Populationnumber Pre-extinctionviralpopulation Quasispecies Rateoffixation(oraccumulation) ofmutations Sequencespace Shannonentropy Specificinfectivity Viralload BasedonDomingo(1999,2003)andEigen(1992). asthebasistocompareextinctionmutagenesiswithsurvival despiteaccumulationofmutationsassociatedwithbottleneck events. Duringcytolyticinfectionsincellculture,lowviralload andlowrelativefitnessfavoredextinctionofFMDVbyFU andAZC.Mutagenizedpopulations,includingpreextinction RNA,didnotshowmutationsintheconsensussequences analyzed,butdisplayedanincreaseinthecomplexityofmu- tantspectra.Themaximumincreasesincomplexityoccurred inthepolymerase(3D)gene,whichisveryconservedin FMDV.Severalaminoacidreplacementsfoundinthemu- tantspectrumof3Dinmutagenizedpopulationshavenever beenobservedinnaturalorlaboratorypopulationsofthevirus (Sierraetal.,2000;Airaksinenetal.,unpublishedresults;re- viewinParienteetal.,2005),suggestingthatoccurrenceof highlydeleteriousmutationsisassociatedwithproximityto theerrorthreshold(Eigen,2002). Thesamemutagenicagentcan
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