The
Brazilian
Journal
of
INFECTIOUS
DISEASES
w w w . e l s e v i e r . c o m / l o c a t e / b j i d
Review
article
Theories
about
evolutionary
origins
of
human
hepatitis
B
virus
in
primates
and
humans
Breno
Frederico
de
Carvalho
Dominguez
Souza
a,
Jan
Felix
Drexler
b,
Renato
Santos
de
Lima
c,
Mila
de
Oliveira
Hughes
Veiga
do
Rosário
a,
Eduardo
Martins
Netto
a,∗aInfectiousDiseasesResearchLaboratory,UniversityHospitalProfessorEdgardSantos,UniversidadeFederaldaBahia,Salvador,BA,
Brazil
bInstituteofVirology,UniversityofBonnMedicalCentre,Bonn,Germany cUniversidadeFederaldaBahia,Salvador,BA,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:Received28September2013 Accepted13December2013 Availableonline13April2014
Keywords: HepatitisBvirus Hepadnaviridae Non-humanprimates Evolutionaryorigins
a
b
s
t
r
a
c
t
Introduction:ThehumanhepatitisBviruscausesacuteandchronichepatitisandis consid-eredoneofthemostserioushumanhealthissuesbytheWorldHealthOrganization,causing thousandsofdeathsperyear.TherearesimilarvirusesbelongingtotheHepadnaviridae familythatinfectnon-humanprimatesandothermammalsaswellassomebirds.The majorityofnon-humanprimatevirusisolateswerephylogeneticallyclosetothehuman hepatitisBvirus,butlikethehumangenotypes,theoriginsofthesevirusesremain contro-versial.However,thereisapossibilitythathumanhepatitisBvirusoriginatedinprimates. Knowingwhetherthesevirusesmightbecommontohumansandprimatesiscrucialin ordertoreducetherisktohumans.
Objective:Toreviewtheexistingknowledgeabouttheevolutionaryoriginsofvirusesofthe Hepadnaviridaefamilyinprimates.
Methods:Thisreviewwasdonebyreadingseveralarticlesthatprovideinformationaboutthe Hepadnaviridaevirusfamilyinnon-humanprimatesandhumansandthepossibleorigins andevolutionoftheseviruses.
Results:TheevolutionaryoriginofvirusesoftheHepadnaviridaefamilyinprimateshas beendatedbacktoseveralthousandyears;however,recentanalysesofgenomicfossilsof avihepadnavirusesintegratedintothegenomesofseveralavianspecieshavesuggesteda mucholderoriginofthisgenus.
Conclusion: SomehypothesesabouttheevolutionaryoriginsofhumanhepatitisBvirushave beendebatedsincethe‘90s.OnetheorysuggestedaNewWorldoriginbecauseofthe phylo-geneticco-segregationbetweensomeNewWorldhumanhepatitisBvirusgenotypesFand HandwoollymonkeyhumanhepatitisBvirusinbasalsister-relationshiptotheOldWorld non-humanprimatesandhumanhepatitisBvirusvariants.Anothertheorysuggestsan OldWorldoriginofhumanhepatitisBvirus,andthatitwouldhavebeenspreadfollowing
∗ Correspondingauthorat:LaboratóriodePesquisaemInfectologia,NúcleoHospitalardeInfectologia,RuaAugustoViana,SN,6oandar,
Canela,Salvador,40110-060,BA,Brazil.
E-mailaddresses:[email protected],[email protected](E.M.Netto).
http://dx.doi.org/10.1016/j.bjid.2013.12.006
prehistorichumanmigrationsover100,000yearsago.Athirdtheorysuggestsaco-speciation ofhumanhepatitisBvirusinnon-humanprimatehostsbecauseoftheproximitybetween thephylogenyofOldandNewWorldnon-humanprimateandtheirhumanhepatitisBvirus variants.Theimportanceoffurtherresearch,relatedtothesubjectinSouthAmericanwild fauna,isparamountandhighlyrelevantforunderstandingtheoriginofhumanhepatitisB virus.
©2014ElsevierEditoraLtda.Allrightsreserved.
Introduction
ThehumanhepatitisBvirus(HBV)isasmallenvelopedDNA virusthatcausestwoformsofhepatitis–acuteandchronic. TheWorld HealthOrganization(WHO)estimatesthatmore than 1/3ofthe worldpopulation already possessserologic evidenceofHBVinfection,350millionpeoplearechronically infectedandapproximately600,000deathsarereportedeach year asa resultofacute or chronic hepatitisB.1,2 Infected
patients have a high risk of developing serious problems relatedtothedisease,suchasfibrosis,cirrhosisand hepatocel-lularcarcinoma(HCC).3Today,HCCisthefifthmostfrequent
humancancer.4,5
Aprophylactic vaccine againsta subunit ofthe hepati-tis B surface antigen (HBs) is already available. However, there can be failures in some cases such as emerging anti-HBs-escapemutantviruses,patientswithcompromised immune-responseorheterologousHBVgenotypes.6–8Despite
thesafety andefficacy ofthedevelopedvaccines,infection withhepatitisBvirus(HBV)continuestopersistasapublic healthproblemandaleadingcauseofdeathfrominfectious diseasesworldwide.HBVcanbedividedintoatleastten geno-types(A–J), distinguishedbymorethan an8%differencein theirgenomicnucleotidesequence.Therearevariationsinthe geographicaldistributionofHBVgenotypes.Whilethe geno-typesA,DandGaredetectedallovertheworld,genotypes B,C,IandJaremostcommoninAsia,genotypeFandHin NativeAmericans,andgenotypeEcanbefoundinWestern Africa.9–11
TheHepadnaviridaefamilyismadeupofgenera Orthohep-adnavirusandAvihepadnavirus.Theformerinfectsmammals andisrepresentedby:HBV(HepatitisBVirus),whichinfects humans;virusessimilartoHBV(suchaswoollymonkeyHBV andorangutan-HBV forexample), whichinfectnon-human primates;Woodchuckhepatitisvirus(WHV)thatcauses hep-atitis in woodchucks, and Ground squirrel hepatitis virus (GSHV) causing hepatitis in squirrels.12,13 The latter infect
birds, including Duck hepatitis Bvirus (DHBV) responsible forduckhepatitisandHeronhepatitisBvirus(HHBV)which causeshepatitisinherons.14–16
General
characteristics
of
Hepadnaviridae
family
Hepadnaviridaefamily membershaveascommon character-isticsatropismforlivercells.Theyalsopossessenveloped virionsandicosahedralnucleocapsid;thegenomeconsistsof
anincompletedoublestrandedDNAwiththeirownDNA poly-merase,whichisalongnegativestrandandashortpositive strand,withthelatterofavariablelength,dependingoneach species.Theyproducesubviralparticles;generatepersistent infectionandreplicatethroughRNAintermediateviareverse transcriptase.17
ThegenomeofhumanHBV(whichistheprototypespecies ofthefamilyHepadnaviridae)hasapeculiargenomic orga-nization withamechanismofasymmetricreplication.This genomeisrelaxedcircularandhasalengthofapproximately 3200basepairsandhasfourregionsofopenreadingframe[s?] (ORF)whichoverlap:Pré-S1/Pré-S2/S,PreC/C,XandP.These genes are responsible for encoding the three envelope (or surface)proteins;small(S),medium(M),andlarge(L), that constitutetheHBVsurfaceantigen(HBsAg),thecoreprotein (HBcAg),thenuclearprotein(HBeAg),Xprotein(thatcanaffect viralreplicationandproliferation,andinterfereincellular pro-cessesofapoptosisandcarcinogenesis)andviralpolymerase (P).18,19 The ORF of the P gene occupies 80% ofthe entire
genomeandencodestheviralDNApolymeraseenzymewhich hasthreeareas:DNApolymerase,reversetranscriptaseand RNAase.Tobetterdescribemutationsinthisgene,thereverse transcriptase domain was sub-dividedinto 7sub-domains, classified A–G.17,18,20 Mutationsinthe Pgenecause alarge
increaseinthesynthesisofviralDNAandgreaterriskofliver carcinogenesis.18
AnothercharacteristicisthathepatitisBisanon-retroviral virusthatusesreversetranscriptaseaspartofitsreplication process,usingthe‘covalentlyclosedcircularDNA’(cccDNA), which serves as a template for transcription of four viral mRNAsandallowsthemaintenanceofchronicHBVinfection inhosts.21
HBV
in
primates
BesideshumanHBV,whichisthemodelspeciesofthefamily, therearevirusesbelongingtothesamefamilythatinfectother primates(Table1).Non-humanHBVgenotypeswerefoundin higherOldWorldprimates.22,23Togetherwiththehigh
diver-sityofAfricanHBVsubgenotypesandrecombinants,thisled tothepossibilitythattheoriginofHBVoccurredinOldWorld primates.23,24Mostisolatesfromnon-humanprimates(NHP)
werephylogeneticallyclosetohumanHBVisolates.Viruses were found in gibbons (Nomascus sp. and Hylobates sp.),25
chimpanzees(Pantroglodytes),26–29gorillas(Gorillagorilla)30and
orangutans(Pongopygmaeus)31(Fig.1).
Theoriginofthesevirusesremainscontroversial. Chim-panzees from different regions ofthe planet appear tobe
Table1–CharacteristicsofpreviouspublicationsaboutHBVinfectionsinprimates:PCRdetection,HBsAg,HBcAb,
genotypesandobservations.
Publications Non-humanprimates species
PCRa HBsAga–HBcAba Genotypesandobservations
Greatmonkeys(apes)
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
Pantroglodytes spp.
51/268 58/810–10/14 chHBV.Evidencefora
recombinationbetweengoHBV andch-derivedHBV
Njouometal.59(Cameroon) chHBV.Recombination
betweenHBVP.t.troglodytes andP.t.vellerosusstrains Makuwaetal.60(Cameroon,
RepublicofCongoandGabon)
chHBV Makuwaetal.61(RepublicofCongo
andGabon)
– Starkmanetal.23(Cameroon–
testedinUnitedKingdom)
chHBV Takahashietal.29(Sierraleoneand
Gabon)
chHBV,thatcanbea recombinationbetween humanHBVandgo/chHBV
Huetal.27(USA) chHBV
MacDonaldetal.28(Cameroonand UnitedKingdom)
chHBV
Huetal.26(USA) chHBV
Takahashietal.51(Liberia) chHBV
Gretheetal.30(Germany) chHBV
Ogataetal.62(USA) HBV(experimentalinfection)
Vaudinetal.63(UnitedKingdom) HBV(PCR)
EichbergandKalter64(USA) HBV(serologicaltests)
Zuckermanetal.65(United Kingdom)
HBV(serologicaltests)
Starkmanetal.23(Taiwan–tested inUnitedKingdom)
Pongopygmaeus spp.
32/104 58/141–1/14 –
Davisetal.66(Canada) –
Warrenetal.31(Indonesia) orHBV
Vaudinetal.63(UnitedKingdom) HBV(PCR)
Salletal.67(Cambodia) Hylobatesspp. 66/211 53/225–48/130 gbHBV
Starkmanetal.23(Taiwan–tested inUnitedKingdom)
gbHBV
Aibaetal.68(Japan) gbHBV
Noppornpanthetal.69(Thailand) gbHBV
Gretheetal.30(Germany,France, Thailand,andVietnam–testedin Germany)
gbHBV
Thorntonetal.70(UnitedKingdom) gbHBV
Lanfordetal.25(USA) HBV(PCR)
Norderetal.71(Thailand–testedin USA)
gbHBV
Vaudinetal.63(UnitedKingdom) HBV(PCR)
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
Gorillagorilla spp.
14/68 5/55–0/14 goHBV.Evidencefora
recombinationbetweengoHBV andch-derivedHBV
Njouometal.59(Cameroon) goHBV
Makuwaetal.60(RepublicofCongo andGabon)
–
Thorntonetal.70(UnitedKingdom) goHBV
Gretheetal.30(Germany) goHBV
Zuckermanetal.65(United Kingdom)
HBV(serologicaltests)
Table1(Continued)
Publications Non-humanprimates species
PCRa HBsAga–HBcAba Genotypesandobservations
Dickens,201378(SouthAfrica) Papiospp. 19/97 0/176–4/111 HBV,subgenotypeA2
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
–
Baptistaetal.72(SouthAfrica) HBV(experimentalinfection)
Michaelsetal.73(USA) –
EichbergandKalter64(USA) HBV(serologicaltests)
Dupinayetal.35(MauritiusIsland) Cercopithecus spp.
0/37 0/121–0/102 –
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
– Makuwaetal.60(RepublicofCongo
andGabon)
– Starkmanetal.23(Cameroonand
Nigeria–testedinUnited Kingdom)
–
EichbergandKalter64(USA) –
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
Mandrillusspp. 1/109 0/252–0/252 Incompletedata
Starkmanetal.23(Cameroonand Nigeria–testedinUnited Kingdom)
–
Makuwaetal.60(RepublicofCongo andGabon)
Miopithecustalapoin – 0/5–0/5 –
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
Cercocebus (Lophocebus) albigena
1/14 0/6–0/6 Incompletedata
Makuwaetal.60(RepublicofCongo andGabon)
–
Makuwaetal.60(RepublicofCongo andGabon)
Chlorocebusaethiops – 0/29–0/29 –
Dupinayetal.35(MauritiusIsland) Macacaspp. 31/120 0/223–0/223 SequencewasclosetoHBV genotypeDsubtypeayw3 Lyonsetal.22(Cameroon–tested
inUnitedKingdom)
–
Lyonsetal.22(Cameroon–tested inUnitedKingdom)
Erythrocebuspatas 0/3 – –
Newworldmonkeys
Lanfordetal.32(USA) Lagothrixlagotricha 10/35 7/31–X WMHBV
EichbergandKalter64(USA) Saimirisciureus – 0/20–X –
EichbergandKalter64(USA) Callithrixjacchus – 0/6–X –
EichbergandKalter64(USA) Saguinusoedipus – 0/12–X –
a Positives/tested.
infected with different types of isolates,27 supporting the
concept that these viruses may have evolved with their hosts.However,thehepadnavirusisolatedfromwoolly mon-keys (Lagothrix lagotricha) – woolly monkey HBV (WMHBV) clearlyisanewmemberoftheHepadnaviridaefamily.32Both
the WMHBV and the New World human HBV genotypes F and H were in a phylogenetic sister-relationship which is more divergent to the Old World human HBV genotypes, strengtheninghypothesesonanoriginofHBVinNewWorld primates.33,34 Untilthepresentmoment,WMHBVhasbeen
detectedonlyincaptiveanimalsatonezoo,butit wasnot foundinanotherfourzoostested.32Sofar,therehavebeen
no reportsabout the presence ofthis virus in wild woolly monkeys.
In2013,Dupinayetal.35investigatedHBVinfectioninsmall
primatesofdifferentoriginsandinMauritius,25.8%(inserum) and42%(inliver)ofHBVDNApositiveswerefound.Genome sequencingdatarevealedthatitwashumanHBVgenotype D,subtypeayw3.Thisprovidesevidencefortheexistenceof smallmodelsimianchronicHBVinfection,immunologically nearhumanandthatit mighthavebeentransmittedfrom manhundredyearsago.
Theories
of
HBV
origins
and
evolution
Withtheadventofthenewfieldofpaleovirology,studieshave revealedthatintegrationintothenucleargenomeofgermline
GER (3 Pub.) JPN (1 Pub.) TWN (2 Pub.) THA (1 Pub.) KHM (1 Pub.) VNM (1 Pub.) IDN (1 Pub.) =1 =1 =1 =1 =1 =1 =1 GBR (3 Pub.) FRA (1 Pub.) USA (8 Pub.) CAN (1 Pub.) =4 =1 =2 =1 =1 SLE (1 Pub.) LBR (1 Pub.) GAB (2 Pub.)
Pan troglodytes spp. Cercocebus (lophocebus) albigena Macaca spp. Lagothrix lagotricha Pongo pygmaeus spp. Hylobates spp. Gorilla gorilla spp. Papio spp. Mandrillus spp. COG (3 Pub.) =1 =1 =1 =1 =1 97 97 98 98 0.02 95 100 100 100 MUS (1 Pub.) HBV/Orangutan/AF193863 HBV/Gibbon/U46935 HBV/Homsap/J/Borneo/AB486012 HBV/Chimpanzee/AF305327 HBV/Gorilla/AJ131567 HBV/ADW2/A/AM282986 HBV/Homsap/B1/Japan/D23678 HBV/Homsap/I/Vietnam/AF241409 HBV/Homsap/C1/Cambodia/AB117758 HBV/Homsap/D/Russia/AB126581 HBV/Homsap/E/Ghana/AB205192 HBV/Homsap/G/AF160501 HBV/Homsap/F4/X69798 HBV/Homsap/H/Nicaragua/AY090454 HBV/woollymonkey/AF046996 ZAF (1 Pub.) CRM (5 Pub.) =1 =1 =1 =1 =1 =1 =1 =1 =1 =1 =1 =1 =1 =1 =1 =1
a
b
Fig.1–(A)Geographicaldistributionofpublicationrelatingtonon-humanprimateswhichweredetectedwithsomeHBV genotype.SampleanimalsarelistedbygenerainTable1.(B)TheevolutionaryhistorywasinferredbyNeighbor–Joining method.74Thepercentageofreplicatetreesinwhichtheassociatedtaxaclusteredtogetherinthebootstraptest(1000
replicates)areshownabovethebranches.75Thetreeisdrawntoscale,withbranchlengthsinthesameunitsasthoseofthe
evolutionarydistancesusedtoinferthephylogenetictree.Theevolutionarydistanceswerecomputedusingthep-distance method76andareintheunitsofnumberofbasedifferencepersite.Allpositionscontaininggapsandmissingdatawere
eliminated.Therewereatotalof3167positionsinthefinaldataset.evolutionaryanalyseswereconductedinMEGAS.77
cells canlead tovertical inheritanceofretroviral genes as hostalleles.Suchintegrationeventsarereferredtoas endoge-nousviralelements(EVEs).Paleoviral“fossils”wererecently discoveredfromawiderangeofvirusesincludingEVE non-retroviral families (rtDNA viruses) e.g.: Hepadnaviridae.36,37
Genomic “fossils”ofavihepadnaviruses integrated into the genomesofdiverseavianspeciessuggest thatthe originof this groupismuch olderdating back several millionyears to the Mesozoic Era.38–40 In a recent study, Suh et al.40
emphasizedthat“insightsintolong-termsequenceevolution, genomeevolution and hypotheticalancestralhostschange theunderstandingoftheprehistoricevolutionof Hepadnaviri-dae,includingthehypotheticaloriginofmammalianHBVs,” contributingtoseveralstudiesinthefieldofmedicaland pale-ontologicalresearch.Theevolutionaryoriginofhepadnavirus
inprimateshasbeendatedbackseveralthousandyears.33No
“fossil”recordshavebeendescribedfromprimatessofar. Mostofourknowledgeaboutpathogenesisandthe repli-cationof hepatitisBvirus hasbeen obtained from studies ofhepadnaviruses related toanimals as models, including DuckHepatitisBVirus(DHBV),41WoodchuckHepatitisvirus
(WHV),42 Ground Squirrel Hepatitis virus (GSHV),43 Arctic
Squirrel Hepatitis virus (ASHV),44 Heron Hepatitis B Virus
(HHBV),45andStorkHepatitisBVirus(STHBV).46
Studiesaboutpathogensthataffectprimatesareofgreat scientific relevance because of their evolutionary relation-ship withhumans. Non-human primates can be sentinels forsurveillanceofinfectiousagentsandalsobiological mod-els for important diseases affecting the human species, such as HBV. Checking for diseases common to humans
and primates is crucial in reducing risks to the health of humans.47
Allknownhepadnavirusesthataffectprimatesandother animalscause acute and chronichepatic infection intheir hosts.48Amaincharacteristicofallthevirusesinthis
fam-ilyisthepossibilityofchronicinfectionwithseriousclinical consequences.48,49However,whataretheimplicationsofthe
originsofHBV?
Duringthe1990s,threecompetinghypothesesaboutthe evolutionaryorigins ofHBV emerged, as reviewedby Sim-mondsin2001.24ANewWorldoriginwasproposedbecauseof
thephylogeneticco-segregationbetweentheNewWorldHBV genotypesFandHandWMHBVinbasalsister-relationship, totheOldWorldnon-humanprimatesandhumanHBV vari-ants.ThedisseminationofHBVintotheOldWorldwouldthen haveoccurredeitherinthe post-ColumbianEra(nearly500 yearsago)orduringearlierhumanmigrationsabout15,000 yearsago.33,34AsecondtheorysuggestsanOldWorldorigin
ofHBV,andthatitwasspreadfollowingprehistorichuman migrationsover100,000yearsago.50Athirdtheorysuggestsa
co-speciationofHBVinnon-humanprimatehostsbecauseof theproximitybetweenthephylogenyofOldandNewWorld NHPandtheirHBVvariants.28
Thesetheoreticalapproacheswereunabletoreconcile con-flictingdataresultantfromthedistributionofHBVvariantsin humanandnon-humanprimatehostsonaglobalscale.An exampleisthattheHBVgenotypesinOldWorldprimatesare mutuallyequidistant.Thisisunlikelytohaveoccurredfrom independentacquisitionsofhumanHBVvariantsinonlyafew hundredyears,goingagainsttheNewWorldorigintheory.24
InrelationtothetheoryofasupposedexodusofHBVtogether withhumanmigrationoutofAfricatootherareasoftheplanet does notexplain the distributionof HBV genotypes inthe world.24Forexample,theNewWorldHBVgenotypeFthatis
foundinNativeAmericansisalsofoundingenetically unre-latedislandpopulationsofPolynesia.Theclosestrelativesof NativeAmericans livinginNortheastern Asiaare predomi-nantlyinfectedbygenotypesBandCofHBV.24
Thewidely host-specific HBV variants support the the-oryaboutHBVco-speciationwithprimatehosts.However,as notedbySimmonds,24thistheoryischallengedbyalackof
sharedHBV variantsbetweenhumansandnon-human pri-mates, bythe existenceofcross-species HBV transmission andbythelackofhigherdiversificationinNHPcomparedto humanHBVvariants.Thesehavelongbeendeemedunlikely, butrecentdatahasshownthatorangutansandgibbons shar-inghabitatsinAsiaharbourphylogeneticallyco-segregating HBVvariants.Similarly,recombinationeventsbetweenHBV genotypesofchimpanzeeandgorillafromCentralAfrica, phy-logeneticallygroupedtogether and inter-species havebeen described.22,23 Furthermore, sporadicdetections of
human-relatedHBVgenotypeshavebeendescribedinchimpanzees and Orangutans, both of the Hominidae family.9,51 Cui52
suggests that a large number of cross-species transmis-sioneventsare probablyalsopresentinavihepadnaviruses, whose phylogeny does not match that of the host orders Gruiformes and Anseriformes.52 Gibbons separated
geneti-cally from orangutans, gorillas and chimpanzees about 20 millionyearsago.Despitethis,theorangutanandgibbonHBV variantsfoundtodatearesimilar.22
Evidenceofanimalsasreservoirs,possiblerecombination betweenhumanandnon-humanprimateHBVvariants,and inter-species transmissions all provide important informa-tionthatmayassistintheeradicationofHBVthroughoutthe world.28
Co-evolution ofHBV variantsinnon-human primatesis furtherchallengedbythe comparabledegreeof diversifica-tion within viruses that affect chimpanzees, gibbons and gorillas,andphylogeneticsister-relationshipsbetweenthese virusesthatdonotreflecttheevolutionoftheirhosts.This includestheabsenceofoutliergorillaHBV variantsin rela-tion tochimpanzee variants and humanHBV genotypes F andHinphylogeneticoutlierpositiontotheOldWorldNHP viruses.22Similarly,thistheoryfailstoexplainthepositionof
gibbonHBVvariantsandtheircomparablediversificationto other primateHBVgenotypes (phylogenetically),whilethey shouldbemorediversifiedthanthoseofgreatapesgiventheir divergencefromthelatterabouttwentymillionyearsago.52
Co-evolutiononthescaleoftheHepadnaviridaefamilyseems evenlesslikely,giventhehighdiversityofrodentandbird hep-adnavirusesfromtheirprimatecounterparts.Asnotedabove, thisdoesnotmatchthetimescaleofthelikelyseparationof thesevariants,whichmaybeonly10–20timesgreaterthan thedevelopmentofmonkey.22
Attemptstodetermineanon-recentHepadnaviridae evo-lution are compromised by several factors. This includes the sequence constraints arising from largely overlapping ORFs.33Whilethistechnicalproblemcanbedealtwith,33there
are severalrecentdescriptionsofavihepadnavirus genomic fossils.38,39,53Thesesequenceshaveindicatedthatprevious
assumptionsbasedonexistentHBVvariantsmayhave under-estimatedtheperiodofhepadnavirusesorigin intherange ofseveralmillionyears.38Theoretically,acontinuous
appear-anceofinfectiousvirusesfromgenomicpocketscouldexplain theunusuallyslowratesofsequencechangeintherangeof 10 persiteper yearobservedthat arenecessary toexplain thesequencedivergencebetweennon-humanprimatesHBV hostsinaco-speciationscenario.24,33
UnderstandingtherelationshipbetweenhumansandNHP variantsofHBVwillhelpexplainthepossiblerolethathumans andotherprimateshaveplayedinthespreadofHBVaround the globe.22 Nohepadnaviruselements inprimate genomic
datahavebeendescribedtodate.Itisclearthatonesingle theoryhasbeenunabletoexplaintheemergenceofHBVuntil now.
Primates
in
South
America
The most plausible scenario to explain the arrival of pri-matesinSouthAmericaconsistsofatransatlanticmigration attheendoftheEoceneepoch.SouthAmericanplatyrrhine primates probably dispersed from either Asian or African catarrhine ancestors about 37–40 million years ago. How-ever,theradiationofplatyrrhinesintheNewWorldprobably occurredduringtheMioceneepoch,52,54althoughthe
feasibil-ityofthisrouteisthesubjectofseveraldebates.Theoldest primatefossildiscoveredinSouthAmericaisdatedtoabout 27 millionyears ago.50 Whether OldWorld hepadnaviruses
Fig.2–Ingreenandyellow,thegeographicdistributionofnon-humanprimates52,54,56,57.Inyellow,Brazilwhichhaslarge
rangeofspeciesandsubspeciesofneotropicalnon-humanprimatesinthewildfauna,representingapproximately21%of thegroupintheworld.56,57
barriersformedbytheseparationofthesub-continentfrom theGondwanansupercontinentabout100millionyearsago28
is something that remains unknown. Hypothetical viruses wouldthenhavebeenpassedtoseveralhostlineages,because aSouthAmericanevolutionofplatyrrhines100millionyears agoisdeemedhighlyunlikely.28
Thehighdegreeofcomplexityinepidemiologicalfactors suchastransmissionroutescanaffectthelargenumberof HBVvariantsincirculation.However,thepropagationofthese viruses can be enhancedwith the development of recom-binant variants,allowing the virus tobe transmittedmore efficientlybetweendifferentspecies.10,55
There are many primates in South America, and in Brazilalone 133 speciesand subspeciesofNeotropical pri-mates can be found in the wild fauna, which represents approximately 21% of the existing group on the planet56
(Fig.2).Wildcyclesandurbancyclesoftransmissionofsome pathogens starttointertwineformingnewepidemiological settingswithriskstohumanandanimalpopulationsinboth environments.57,58
Untilnowtherehasbeennostudyintoinfectious hepad-navirusinnon-humanprimatesofthefaunainSouthAmerica anditisnotknownwhethertheexistingspeciesintheNew WorldmayormaynotbecarryingthehepatitisBvirusthat infectshumans,orifitisanothervariantofthe Hepadnaviri-dae family.Therefore, to investigate the presenceofthese virusesinthisareaitisimportanttotrytohelpunravelthe ori-ginoftheHepadnavirusesandhowtheyevolvedinprimates andhumans.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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