ASTROBIOLOGYSCIENCECONFERENCE2006Washington,DCMarch25–31,2006ViralEvolution03.29.06HEPATITISBVIRUS:COMMENTSONVIRALANDHUMANEVOLUTIONBaruchS.BlumbergFoxChaseCancerCenterPhiladelphia,PA,19111,USA1. HepatitisBVirusisaverycommonvirus.2. Humanshavebeeninfectedwithvirusforaverylong time,possiblyfromthetimeoftheoriginofhumans.3. VirusescloselyrelatedtoHBV(“Hepadnaviruses”)are knowninmanyspeciesotherthanhumans.4. HBVisamajordeadlyinfectiousagent.5. Malesaremorelikelythanfemalestobecomechronic carriersofHBVandtodieasaconsequence

ofinfection.6. HBVrelateddeathsarehighestinoldermales;high HBVprevalencedecreasesthemaletofemaleratioin olderagegroups.7. Thereareaseriesofpolymorphismsthataffect

susceptibilitytochronicinfection.8. ParentswhoarecarriersofHBVhaveahigherratioof

malestofemalesintheirnewbornoffspringthando

parentswhohaveantibodyagainstthesurfaceantigen

ofHBV;highHBVincidenceincreasesthemaleto

femaleratioatbirth.9. Theremaybehostadvantagestothecarrierstate.10. Theworldwidevaccinationprogramisdecreasingthe

prevalenceofHBV.11. Virussequencesareverycommoninthehumangenome.12. HBVasan“engine”ofhumanevolution.13. Werevirusesanearlyformoflifeand,possibly,the

earliestform?PrimaryCanceroftheLiverWorldwide:ThirdmostcommoncauseofdeathfromcancerinmalesSeventhmostcommoncauseofdeathfromcancerinfemalesMorethanamilliondeathsperyearHepatitisBvirus(about85%)andhepatitisCvirusaccountformostofthesecancersManyotherfactorsinvolvedinthepathogenesisHumanHepatitisViruses

GenomeVirusGenome Size(Kb) Envelope ClassificationHAV RNA 7.5 - Picornavirus

(Hepatovirus)HBV DNA 3.2 HBsAg HepadnavirusHCV RNA 9.4 + Pestivirus-or

Flavivirus-likeHDV RNA 1.7 HBsAg UnclassifiedHEV RNA 7.5 - Claicivirus-like

orAlpha-like

supergroupHBVisoneofthemostcommoninfectionsintheworld.About600,000to1,000,000deathsperyearareattributabletothediseasesassociatedwithHBV.(H.Margolis,CenterforDiseaseControl.PaperpresentedatThird

InternationalConferenceonTherapiesforViralHepatitis,Maui,12/12/99)VirusNumberInfected(Millions)Low15%34CaseFatalityRateTotalDeaths(Millions)High25%100%371HIVHBV3492.855.7PREDICTEDDEATHSFROM

PREVALENTCARRIERSOFHIVANDHBV“HepatitisBisaviralinfectionoftheliver.Morethantwothousandmillion(2billion)peoplealivetodayhavebeeninfectedwiththehepatitisBvirus.Approximately350millionarechronicallyinfectedandareathighriskofseriousillnessanddeathfromcirrhosisoftheliver

andprimarylivercancer.

HepatitisBispreventablewithasafeandeffectivevaccine—thefirstvaccineagainstcancer.”

WHOwebsite,20040500100015002000250025-3435-4445-5455-6465-74Agegroup(years)Mortalityper100,000pyMHBV+MHBV-FHBV+FHBV-MORTALITYBYAGE,GENDERANDHBVRESPONSEHAIMENCITY,CHINAG.Chen,W.Lin,F.Shen,U.Iloeje,T.LondonandA.EvansInter.J.ofepid.2004,inprintHEPATITISBVIRUSMORPHOLOGYCharacteristicsNucleicacid:DNAClassification:

hepadnavirustype1Serotypes:multipleInvivoreplication:

reversetranscriptionin

liverandothertissuesInvitropropagation:

primaryhepatocyte

cultureandtransfection

byclonedHBVDNA42nm22nmCHBsAgHBcAgHBVDNAHEPATITISBLIKEVIRUSES

HepadnavirusesHuman Homosapiens HBVGorilla Gorillasp. HBVChimpanzee Pantroglodytes ChHBVGibbon FamilyHylobatidae HBVOrangutan Pongopygmaeus HBV Woollymonkey Lagothrixlagotricha WMHBVTreeshrew Tupaiabelangeri HBV(Kangaroo FamilyMacropodidae KHV)WoodchuckorGroundhog Marmotamonax WHVBeecheygroundsquirrel Spermophilusbeecheyi GSHVArcticsquirrel S.parryikennicotti ASHBVRichardsongroundsquirrel S.richardsonii RGSHV(Treesquirrel Sciuruscarolinensis THBV)Pekinduck Anasdomesticus DHBVGreatblueheron Ardeaherodias HHBVGreyheron A.cinerea HHBVSnowgoose Ansercaerulescens SGHBVRoss’goose A.rossii RGHBV WhiteStork Ciconiaciconia STHBV Demoisellecrane Anthropoidesvirgo CHBVGreycrownedcrane Balearicaregulorum CHBV(Stinksnake Elaphecarinata SSHV)(Itemsinparentheseshavenotbeenvalidated.Treeshrewswereexperimentallyinfected.)CONTROLOFHEPATITISBVIRUSINCHINAZ.Y.Xu,T.Q.Yan,S.J.Zhao,etal.ShanghaiMedicalUniversity“InfantHBVimmunizationhasbeenimplementedintopublichealthserviceinChinasince1986…theseropositivityforHBsAgwasreducedfrom16.3%(879/5397)ofhistoricalcontrolsto1.43%(70/4886)incross-sectionalstudyand1.81%(210/11582)inacohortstudy.”IntheUnitedStates,thenumberofnewHBVinfectionsperyearhasdeclinedfromanaverageof260,000inthe1980stoabout78,000in2001.Thehighestrateofdiseaseoccursinthe20-49agegroup.GreatestdeclineistheconsequenceoftheroutineHBVvaccinationprogramamongchildrenandadolescents.

Thereareanestimated1.25millionchronicallyinfectedAmericans,ofwhom20-30%acquiredtheirinfectioninchildhood.CDCWebsite,2004HBVVACCINATIONINTHEUNITEDSTATES Auniversalchildhoodvaccinationprogram wasundertakenbetween1981and1983in NativeAmericansinAlaska,USA (McMahon,etal.,1996).

AcutehepatitisBinfectiondroppedfrom215 cases/100,000beforethevaccination program,to7to14casesin1993afterthe programwasinplace. In1995,nocaseswerereported.HBVVACCINATIONINALASKA,USAAsofMay2003,151(79%)of192nationalmembersoftheWHOhaduniversalchildhoodvaccinationprograms.Thereare89memberstatesthathavebeendesignatedashavingahighprevalenceofHBVcarriers.Sixtyfour(72%)haveuniversalinfantvaccinationprograms.ItisthegoaloftheWHOtohavevaccinationprogramsinallcountriesby2007.

HepatitisBVirusWorldwideVaccinationProgramDistributionofAustraliaAntigen(HBsAg)byGenderMarshallIslands,USTTPIMaleFemaleTotalCebu,PhilippinesMaleFemaleTotalManila,PhilippinesMaleFemaleTotalCashinahua,PeruMaleFemaleTotalTotalNumber24322649543033476413859197454489NumberPositive19143327103763910616PercentPositive6.33.04.622.213.618.0Blumberg,etal,Amer.J.HumanGenetics18,594,1966

Parent’sresponseToHBVEitherparentHBsAg+: anti-HBs–BothparentsHBsAg-: anti-HBs–BothparentsHBsAg-: eitherparentanti-HBs+Couples(No.)3329154LivebirthsMaleFemales60(1.8±0.2)51(1.8±0.2)24(1.6±0.1)24(0.7±0.1)35(1.2±0.2)22(1.4±0.1)Sexratio250(161,429)*146(96,230)*109(91,131)*PLATI,GREECE.NUMBEROFMALEANDFEMALELIVEBIRTHSACCORDINGTOTHERESPONSESTOHBVOFPARENTS*Inparentheses,the5percentconfidencelimits.Blumberg,B.S.SexdifferencesinresponsetoHepatitisBVirus,

ArthritisandRheumatism,22,

1261,1979HepatitisBandSexRatio:IndividualLevelEstimatesNotes:Thistableshowssexratiosamongthechildrenofcarrierandnon-carrierparentsinfourregions.Datawerecollectedbytestingmarriedwomenand,inallcasesexceptforGreenland,theirhusbandsforHBV.Detailedreproductivehistorieswerealsocollected.Thetablerepresentsallbirthstowomeninthosesamples,withgenerallymorethanonebirthtoeachwomen.Thelasttwostudies(Greece2andFrance)weredesignedspecificallytotestthehypothesisthatHBVaffectsoffspringsexratio,andwererunaftertheoriginaltheorywasexpressed.LocationGreenlandGreenlandKarKarIslandKarKarIslandGreece1Greece1PhilippinesPhilippinesGreece2Greece2FranceFranceHBVStatusPositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegativeSons6417463163852876630452100620149

601945420646255413013095512122SexRatio1.070.901.170.791.851.131.611.011.731.051.661.22DaughtersFromOster,E.2004Notes:Sexratioisnumberofboysforeachgirl.Onlycountrieswithmorethan15,000peopleusedtocaclulateHBVpravalenceareincluded.CitationsforeachcountryareinAppendixB.SexRatioatBirthSEXRATIOANDHEPATITIS,WORLDHepatitisRate(%)BrazilBelarusBangladeshIranMalaysiaSingaporeIsraelPakistanChinaMexicoTurkeyFranceIrelandGreeceSouthKoreaSpainAustraliaItalyPolandJapan1.081.061.041.0210246810121416Oster,E.,HepatitisBandtheCaseoftheMissingWomen,Presentation,October12,2004N.Amer&W.EuropeEFFECTSOFVACCINATIONPROGRAMALASKA?HighHBVprevalenceamongAlaskanNative

Americans;lowamongnon-NativeAmerican?Universalvaccinationprogram(includingcatch- up)institutedinearly1980s.Oster,E.,HepatitisBandtheCaseoftheMissingWomen,Presentation,October12,20041996-20021991-19951986-19901980-1985CHANGESINSEXRATIOINALASKABEFOREANDDURINGVACCINATIONPROGRAM21.11.081.061.041.021NativeAmericanHighHBVNativeAmericanLowHBVNon-NativeAmericanOster,E.,HepatitisBandtheCaseoftheMissingWomen,Presentation,October12,2004?HBVexplainsabout50%ofthemissingwomenoverall: over90%inChina,11%inIndia?VaccinationprogramsappeartodecreasesexratioOster,E.,HepatitisBandtheCaseoftheMissingWomen,Presentation,October12,2004MicroorganismGeneAffinityClustersMicroorganismGeneAffinityClusters(cont.)HBVandIroninDown’sSyndromePatientsWithandWithoutHBsAgIncreasedHemoglobin,Hematocrit,SerumIronanddecreasedTotalIronBindingCapacity(TIBC)in20Down’sSyndromepatientswithserumHBsAgcomparedto20without.Thedifferencesaresignificant.HBsAg(+)MeanSDHBsAg(+)MeanSDHemoglobing/100ml15.21.414.91.4Hematocrit%44.23.843.53.6SerumIronmg/100ml163.7TIBCmg/100ml250.4108.2356.8144.8Sutnick,Blumberg,Lustbader.Ann.Int.Med.81,855,1974SerumIronLevels(mg/dl)SerumIronlevelsin1)PatientswithDown’sSyndrome2)Patientsonrenaldialysisand3)ResidentsofaruralcommunityinSenegal,WestAfrica.BlumberginSzentivanyiandFriedman,Editors,Viruses,ImmunityandImmunodeficiency,Plenum1986HBsAg(+)HBsAg(-)NumberDownsSyndromeMale Female164 -84 -40 -Total1648440RenalDialysisMale Female114 21498 10040 117Total145100220SenegalMale Female77 8175 5881 112Total7965193Largenumbersofretroviralsequences(includingthoseofHBV)arefoundinthehumangenome.Theseareoftenthe“fossil”recordofvirusesthatwereincorporatedintothegermlineinpreviousgenerations.Itisestimatedthat8%ofthemodernhumangenomeismadeofretroviralsequences,alargernumberthanthecodingsequences,andtheyareoftenhighlyconserved.ModifiedfromBlumberg,B.S.2005,HepatitisBvirus.Conjecturesonhumaninteractionsandtheoriginoflife,in,“LifeAsWeKnowIt”,Volume10oftheseries“CellularOrigins,LifeinExtremeHabitatsandAstrobiology”editedbyJ.Seckbach,Springer,Dordrecht,NL.;andKilbourne,E.D.(2004).Viruspaleontology,disease,andevolution:anintroduction.Proc.Amer.PhilosophicalSociety148:261andfollowingarticles.

?HepatitisBvaccinationisoneofthelargestworldwidediseasepreventionprograms.?IthasdecreasedthespreadofHBV,particularlyinChinaandEastAsia.Ithassignificantlydecreasedmorb