Re-emergence of human T-lymphotropic viruses in West Africa

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Review

article

Re-emergence

of

human

T-lymphotropic

viruses

in

West

Africa

Nneoma

Confidence

JeanStephanie

Anyanwu

_,

_Elijah

_Ekah

_Ella

_,

Aghogho

Ohwofasa

_,

_Maryam

_Aminu

a_{AhmaduBelloUniversity,FacultyofLifeSciences,DepartmentofMicrobiology,Zaria,Nigeria} b_{COMSATSUniversity,DepartmentofBiosciences,Islamabad,Pakistan}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received4March2018 Accepted7May2018 Availableonline5June2018

Keywords: HTLVinWestAfrica Worldwidedistribution Epidemiology HAM/TSP Seroindeterminateindividuals Bloodtransfusion ATLL

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b

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HumanT-lymphotropicviruses(HTLV)areDeltaretrovirusesthatinfectmillionsof individu-alsworldwideviathesametransmissionroutesasHIV.Withtheaimofexposingthepossible re-emergenceofHTLVinWestAfricasincediscovery,asystematicreviewwascarriedout, focusingonthedistributionofthevirustypesandsignificanceoffrequentindeterminate reports,whilehighlightingtheneedformandatoryroutinebloodscreening.Capturing rel-evantdatafromdiscoverytilldate,sourcessearchedwereGoogleScholar,CrossRef,NCBI (PubMed),MEDLINE,ResearchGate,Mendeley,abstractsofConferencesandProceedings, organizationwebsitesandreferencelistsofselectedpapers.Atotalof2626referenceswere initiallyretrievedusingsearchterms:WorldwideprevalenceofHTLV,HTLVinAfrica,HTLV inWestAfrica,HTLVsubtypes,HTLV3and4inAfrica,HTLVofAfricanorigin,HTLV seroin-determinateresults,SpreadofHTLV.Thesereferenceswererigorouslytrimmeddownto 76.AlthoughevidenceshowsthatHTLVisstillendemicintheregion,WestAfricalacks recentepidemiologicalprevalencedata.Thoroughinvestigationsareneededtoascertain thetruecauseofindeterminateWesternBlotresults.Itisimperativethatroutinescreening forHTLVsbemandatedinWestAfricanhealthcarefacilities.

©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Introduction

Human T-lymphophotropic virus (HTLV), formerly called human T-cell lymphotropic virus or human T-cell leukemia/lymphoma virus,is a member of the Deltaretro-virusgenus.TheDeltaretrovirusesbelongtotheRetroviridae

∗ _{Correspondingauthor.}

E-mailaddress:anyanwunneomaconfi[email protected](N.C.Anyanwu).

family andincludebovineleukemia virus(BLV)and simian T-lymphotropicvirus(STLV),asideHTLVs.1

Retroviruseswerenotisolatedfromhumanspriorto1979. Hence, HTLV (type 1) was the first humanretrovirus tobe isolated1 _{from a patient with cutaneous T-cell lymphoma.} HTLV(type2)wasisolatedafewyearslaterfromapatientwith hairycellleukemia.2 _{ItwasthenbelievedthatHTLV-2could}

https://doi.org/10.1016/j.bjid.2018.05.003

1413-8670/©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

References retrieved via Database search and other sources N=2626

References after removal of duplicates N=1088

Titles and abstracts screened focusing on keywords

N=134

Removed = 954 Reasons: duplicate, non-English, non-Human related and in-vitro studies, study

suitability

Full-texts reviewed N=76

Removed=58

Reasons: similar reports, non-Pubmed or Crossref indexed studies, unextractable data

Id en ti fi cat ion Sc ree ning E ligibilit y In cl u d e d

Fig.1–PRISMAflowchartofreviewedstudies.

beassociatedwithhairycellleukemia.However,thefailureto isolateHTLV-2fromreplicablenumberofhairycellleukemia patientsprovedthatitwasnottheetiologicalagentofhairy cellleukemiabutrather,apassengeragent.

Thethirdandprobablythemostimportantretroviruswas discovered a year later and placed in the same genus as HTLV-1and2viruses.Uponsubsequentresearchhowever,it wasrenamedhumanimmunodeficiencyvirusandreclassified undertheLentivirusgenus.In2005,researchersdiscovered two(2)newHTLVtypes–HTLV-3andHTLV-4.3,4_Knowledge aboutthesevirusesislimitedasfewcaseshavebeenreported, comparedtoHTLV1and2.

HTLV1isendemicinsomepartsoftheworld (Southwest-ernJapan,SouthAmerica,theCaribbeanBasin, theMiddle East,Australo–Melanesia,theWestIndies,Jamaica),aswellas equatorialAfrica,5whereWestAfricalies.HTLV-2isendemic inpocketsofpopulations.Withtheaimofexposingthe possi-blere-emergenceofHTLVinWestAfrica,thisreviewfocuses onthedistributionofthevirustypes,pointsoutthe signif-icanceoffrequentindeterminatereports,whilehighlighting theneedformandatoryroutinebloodscreeningpriortoblood donationand/ortransfusion.

Methodology

PreferredReportingItemsforSystematicReviewsand Meta-analyses(PRISMA)wasusedtoreporttheidentifiedstudies. GoogleScholar,CrossRef,NCBI(PubMed),MEDLINE,Research Gate,Mendeleyweresearchedfromdatabaseinceptionuntil February 2018. Abstracts of Conferences and Proceedings, organizationwebsitesandreferencelistsofselectedpapers were also searched. Search terms were: Worldwide preva-lence ofHTLV, HTLV inAfrica, HTLV inWest Africa,HTLV subtypes, HTLV 3 and 4in Africa, HTLV ofAfrican origin, HTLV seroindeterminate results, spread of HTLV. The first

100sourcesidentifiedbyCrossref andGoogleScholarwere screened.Duplicatetitleswereremoved(Fig.1).Eligible stud-ies includedoriginal reports from prevalence studies,case studiesandcohortstudies.Titlesandabstractsrecoveredin thesearchwerescreenedforstudysuitability,focusingonthe keywords;non-English,non-Humanrelated,andin-vitro stud-ieswereexcludedatthispointandfull-textcopiesofpapers thatpossiblydealtwiththereviewtopicwereretrieved.Same reportsofalreadyreportedpopulationbyanotherstudywere alsoexcluded.Theretrieveddatawerescreenedandextracted byNCJandcheckedindependentlybyA,EEandMforany dis-cordance.Studycharacteristicsarepresentedinfigures and table.

Worldwide

distribution

of

HTLVs

The HTLV-1 and 2 viruses have experienced gradual but considerablyconsistentincreaseinprevalencesincetheir dis-covery.HTLV-1subtypesareassociatedwithspecificregionsof theglobe(Fig.2),whileHTLV-2subtypesarerelatedtohighly specificsubpopulations(e.g.BrazilianIndians)andbehaviors suchasinjectiondruguse(Fig.3).

There aresevengeographical orethnic-relatedsubtypes ofHTLV-1including theCosmopolitan subtypeA withfour (4)subgroups,theCentralAfricansubtypeB,theAustralo– MelanesiansubtypeC,theCentralAfrican/Pygmiessubtype D,theCentralAfricansubtypesE(alsoinSouthernAfrica),F, andGrespectively.5_{HTLV-2hasfourknownsubtypes–A,B,} C,andD.

Levine etal.6 _{carried out astudy onthe worldwide} dis-tribution ofHTLV-1 virus on 43,445participants (excluding endemic regions of Japan) and reported a prevalence rate of3.7%.Accordingtothestudy,thehighestprevalencerate of 11.2% was seen in Hawaii, which was closely followed byWest/CentralAfricawithaprevalencerateof10.0%.The Caribbeanbasinhadaprevalencerateof5.1%whiletheother

TC TC TC TC TC TC TC TC TC B B Subtype B Subtype C Subtype D STLV-1 Transmission from Non-Human Primates to Humans Subtype E Subtype F Subtype G F NHP NHP NHP NHP C C D F G E C C C H H H H E G D TC TC TC TC TC TC TC TC TC TC TC TC TC Ajp Ajp Ajp Ajp Ajp Ajp Awa Awa Awa Transcontinental Subgroup Japaneese Subgroup West African Subgroup North African Subgroup

Cosmopolitan Subtype A Ana Ana Awa TC TC TC TC

Fig.2–GlobaldistributionofHTLV-1subtypes.

Source:GessainandCassar.5

3000 km (equat.) 2000 mi (equat.) HTLV 2 Spread HTLV 2a HTLV 2a HTLV 2c HTLV 2d

Fig.3–GlobaldistributionandspreadofHTLV-2subtypes.

countriescapturedinthestudy hadprevalencerateslower than3.7%–SouthAfrica(3.5%),Central/SouthAmerica(2.9%), non-endemicregionsofJapan(2.8%),MiddleEast(2.2%),Asia

(excludingJapan–1.4%),ContinentalNorthAmerica (1.2%), with Europe having the least prevalencerate of 1.0%.The prevalence ofHTLV-1 isdifferent for differentparts of the

world.Itisgenerallycategorizedintothreestrata–regionsof low(lessthan1%),averageormoderate(1%to5%),andhigh (greaterthan5%)prevalencerates.Europehasbeencaptured inmany epidemiological studies,with mostofthe studies focusingon the UnitedKingdom, France and Spain.5 _Most ofthepeoplediagnosedwithHTLVwereeitherbornin–or had genetic affiliationswith Afro – Caribbean and African origin,indicatingthat HTLVinfections and/or transmission maybelinkedtohumanmigration.InAsia,theprevalenceof HTLV-1hasbeenreportedtobebetween0.098%and2.12%in endemicareasofIranand0.3%and37.0%inendemicareasof Japan.5,7,8IrrespectiveofthefactthatJapanisbeingbordered byPRChina,NorthandSouthKorea,thePhilippines, North-ernMarianaIslands,andtheRepublicofChina(Taiwan),these countriesarelargelyfreefromHTLVinfection,suggestingthat thevirusisnottransmittedbymigrantsfromtheseregions, thusrulingouthumanmigrationasthecauseofendemicity inJapan.

TheglobaldistributionofhumanT-lymphotropicvirus2 (HTLV-2)isnotaswidespreadasHTLV1,asitisfoundtobe presentinpocketsofpopulations.Thevirusiscommonamong intravenousdrugusers(IDUs)inEire,Spain,Italyand Scan-dinavia,lesscommon intheUK,and rareinGermanyand France.9,10_{SubtypesAandBareendemicinIDUsand} indige-nouspeopleofinNorth,SouthandCentral(Latin)America, EuropeandAsia(Vietnam,ItalyandSpain),10_andoccur spo-radicallyinpartsofWestandCentralAfrica–Ghana,Gabon, Cameroon,whereitwasfirstisolatedandDemocratic Repub-licofCongo(DRCongo)amongthepigmytribes.2_SubtypeC, whichisadistinctmolecularsubtype,wasisolatedfromthe AmazonregionoftheBraziliansub-cluster,whilesubtypeD, distinctandgeneticallydifferentfromtheothersubtypeswas isolatedfromCentralAfricanCongoleseEfeBambutipygmy.10 ItispossiblethatHTLV-2wasintroducedintotheIDUs popu-lationoftheUnitedStatesduringthe1970s,andintoEurope, slightlylater.

Both HTLV-1 and 2 have been found to be involved in increasingepidemicinsomefactionsoftheworld.However, HTLV-2spreadand/orprevalenceismorecommonthan HTLV-1 in the United States, although the overall prevalence is 200per 100,000 population.11 _{Generally, the highest} preva-lenceofHTLV-1isfoundinJapan(37%)whileLatinAmerica is estimated to have the lowest prevalence (0.024–1.00%). AmpleepidemiologicalstudiesinTurkeyare lackinghence, theinabilitytocategorizeits stratumofprevalence.Onthe otherhand,HTLV-2(subtypeC)ismostendemicamongthe indigenouspeopleofBrazil,hence,theBrazilianAmazonis thehighestarea ofitsendemicityintheworld.9_An alarm-inglyhighHTLV-2prevalenceofup to61% hasbeen found inVenezuelaamongtheYaruroandGuahibopopulations9,10 whileupto3.8%prevalencehasbeenfoundinPeruvian Ama-zon.

SeroprevalenceofHTLV-1ismorepredominantinfemales thanmales,indicatingthatfemalesare moreatriskofthe retroviralinfection.1Verticaltransmissionhowever,accounts for higher male predisposition to HTLV-1 seropositivity at childhood. The ratio of adult T-cell leukemia/lymphoma (ATLL)is2:1inmalesand femaleswhilethe reverseisthe caseforHTLV-1-associatedmyelopathy(HAM)/tropical spas-ticparaparesis(TSP).12_{Itisratherdifficulttodeterminethe}

genderdistribution ofHTLV-2because ofthe peculiarityof thestudypopulations,althoughithasbeenassociatedwith the femalegenderinthe UnitedStates.9 _{Theprevalenceof} thevirusesishigherinolderage,majorlyduetotheirlong latencyperiod. Thetime ofexpressionofthe viruses lead-ing tomalignant or neurologicaldisorders,however, varies withindividuals.ATLLismostlyrapidlyprogressiveandfatal, withmediansurvivaltimeoftwoyears.HAM/TSPmayensue asearlyasfivemonthsaftertransfusion-transmittedHTLV-1 infection.

Thereseemstobeanoveralldeclineintheworldwide dis-tributionofHTLV-1virusfrom10–20millionto5–10million.5 Thereasonforsuchwidegapanddifferenceindistribution maybeduetothefactthatlargeregionshadnotbeen inves-tigated,fewpopulation-basedstudiesareavailable,andthe assaysusedforHTLV-1serologywerenotspecificenoughat thetimeofearlyepidemiologicalstudies.5_{Itshouldhowever,} benotedthatthereisstillalargeamountofdatayettobe cap-turedinsomeareasoftheworld,ashighlypopulatedregions includingEastAfrica,China,India,andtheMaghreb,are hith-erto yettobeexhaustivelysurveyed.Hence,theworldwide distributionofHTLV-1maybeslightlyorwellabove10 mil-lioninfectedindividuals.Furthermore,thetrueprevalenceof HTLV-1 worldwidehasnot been coveredpreviouslyas epi-demiologicalstudiesmostlycoveronlyblooddonors,pregnant women,orhospitalbasedstudiesofdifferentselectedpatients orhigh-riskgroupssuchasIDUs,HIV,andotherhematologic patients, neurologicpatientsorprostitutes,ratherthan the generalpopulation(villages, towns,cities, states,provinces regionsorgeo-politicalzonesofacountry).

DistributioninAfrica

Molecular phylogenetic analyses have traced HTLV-1 to zoonotic origin with inter-species transmission from non-humanprimatestohumans13_{duringtheupperPaleolithicera;} andtranscontinentalspreadfromAfricatoAustro-Melanesia and Asian,downto Northand SouthAmerica (Fig.2).The molecularcharacterizationofHTLV-2isolatedfrom Cameroo-nianpygmytribesalsosupportedtheirAfricanorigin,similar to HTLV-1 (Fig. 3). HTLV infections have been identified in variousregions,especiallythesub-SaharanAfrica.Themost affectedareasareEastAfrica,CentralAfricaandWestAfrica. ReportonAfricashowsHTLV-1prevalencetobebetween6.6% and8.5%inGabon,1.05%inGuinea,3.2%inCongo,5.5%in Nigeria,2.7%and19.5%inKenyanwomen.14_{Theprevalence} liesbetween0.5%and4.2%inGhana,0.9%inCameroon,1.5% inMozambique,0.6%inCentralAfricanRepublic,1%inSouth Africa,5_{0.63%inMalawi,}15_{and>15%inSeychelles.}16

TheinitialisolationsofHTLV-2inAfricanpopulationwere frompygmytribesbothfromEthiopiaandWestAfrica.2,17_The identificationofHTLV-2–likeprimatevirusinCentralAfrica suggests thatthe virus,likeHTLV-1,originatedfromAfrica. However,itismorewidespreadthroughouttheAmericasthan the African population,raising afew questions.A serosur-veyacrossAfrica2_{establishedHTLV-2prevalenceratesof14%} fromBambutipygmiesinDRCongoand2.3%frompygmies inCameroon.HTLV-2subtypeBhasalsobeencharacterized from Gabonesefamily,18 _{aswell asCameroonian pygmyof} Bakolatribe.WithanexceptionofareportofHTLV-2infection

inanewworldprimateinMongolia,thereisnopopulation basedevidenceofthevirusmigratingfromOldworldtothe Newworld.OtherreportsofHTLV-2infectioninclude:0.1–0.5% inGabon,19–22 _6.47%23 _and0.1%24_{inGhana (Table1),0.08%} inGuinea-Bissau,25,26 _{0.5–3.3% inNigeria}27–29 _{and 0.02% in} Senegal.30

DistributioninWestAfrica

HTLV and associated diseases are not regarded as public healthprobleminWestAfrica,andarethusneglected. How-ever,severalstudieshavereportedhighprevalence(from0% to25%)ofHTLVinfection.

Nigeria

In 2011, Terry et al.31 _{found 3.6% seroprevalence of HTLV} among blood donors in Oshogbo, South-Western, Nigeria. Durojaiyeetal.32_{found0.5%prevalenceamongblooddonors} atatertiarycenterinLagos,Nigeria.Alltheenlisteddonors hadnohistoryofbloodtransfusion;hence,noassociationwas establishedbetweentransfusionhistory andHTLV seropos-itivity.A cross-sectionalstudy carriedout inSouth-eastern Nigeria1_{showedaprevalencerateof0.5%inpregnantwomen.} InSouth-Western Nigeria,analarminglyhighprevalenceof 22.9%and16.7%wasobservedamongcommercialsex work-ers(CSW) and pregnant women, respectively,33 _while5.1% prevalencewasfoundinhighschool students.High preva-lence ratesof25.8% and 24.2%were alsoidentified among blooddonors34_{andpregnantwomen.}35_{Zeroprevalencehas} alsobeenreportedinsomeNigeriancohorts.32,36–39_Thisisan indicatorthattheprevalencerateofHTLV inNigeriavaries withlocation.CasesofdualinfectionwithbothHTLV1and2 havealsobeenreportedinNigeria.27,28Thereislimiteddata onHTLV-2inNigeriaascomparedtoHTLV-1.27–29_Thiscouldbe becauseHTLV-1hasreceivedmoreresearchattentionin epi-demiologicalandcasestudies,hencebeingthemorestudied virustype.ItcouldalsobethatHTLV-2wasnotfoundinthe HTLV-1and2pooledstudies,indicatingthatthevirus type mayhavelittleornoprevalenceintheNigerianpopulation. TherearenoreportedcasesofHTLV-3orHTLV-4infectionin Nigeria.ThecompletelistofHTLVprevalenceasreportedby differentauthorsisfoundinTable1.

Ghana

TheprevalenceofHTLV-1wasassessedintwocommunities intheGhanaianpopulationafewyearsafterthediscoveryof thevirus.40_{Theprevalencerateswere3.6%and4.0%inurban} andruralpopulations,respectively.Prevalenceincreasedwith age(being5.9%amongpersonsaboveI0yearsofage)butdid notshowanydifferencewithsex.Apopulationbasedstudy carriedoutbetween1989and1990detectedthepresenceof HTLV-1in Ghana.41 _{The specificprevalence ratewas} how-ever,difficulttodefineduetohighfrequencyofindeterminate resultsonwesternimmunoblotting.Theseropevalencewas foundtobebetween1and2%,withnoassociationbetween infectivityandmalignancyorsexualbehavior(prostitution). ThereportedseroprevalenceofHTLV-1amonghealthy Ghana-ian blood donors has been stated to be between 0.4 and 4.2%.24,42_Armahetal.24_{foundHTLV-2prevalenceof0.10%and} 0.21%HTLV-1/2amongpregnantwomen.Laletal.23_reported

29.49%HTLV-1prevalenceand6.47%HTLV-2prevalencefrom reactiveindividualsofpreviousserosurvey,while3.59% posi-tiveswereuntyped(Table1).HTLVco-infectionwithHIVhas alsobeenseeninGhana43_(Fig.5).

Guinea-Bissau

Studieshaveshown3.60%,26.19%,and2.60%HTLV-1 preva-lence among urban adult population, STD patients, and pregnant women of Guinea-Bissau, respectively.26,44,45 _van Tienenetal.46_{reportedHTLV-1prevalencetobe5.2%in1990,} 5.9%in1997and4.6%in2007,whilenotingacontinued asso-ciationwithHIV(Table1).Inasurveycarriedoutontherural population,itwasdiscoveredthattheCosmopolitanHTLV-1 1aDsubtypewaspredominant47_{intheruralBissau} commu-nity.HTLV-1co-infectionwithHIV-2hasbeenobservedamong hospitalizedpatients,policeofficers,andpregnantwomenin Guinea-Bissau48aswellasinruralpopulationstobe≤15%. ThereishighermortalityinHIV-2/HTLV-1co-infectedpatients withtuberculosiscomparedtotheirHTLVseronegative coun-terparts,asthemedianCD4+countishigherintheformer. TheendemicityofHTLVhasdeclinedtoabout2%.

Benin

BeninRepublicwasnotunaffectedbytheearlyendemicityof HTLV-1/2,asaprevalencerateof1.5%wasreportedbetween 1988and1989inapopulationbasedstudy.49_{Prevalencewas} lower in coastalregion than inthe north.Subsequent sur-veyinthenorthobserved1.86%seroprevalenceofHTLV-150 amongapparentlyhealthyindividualsofthegeneral popula-tion,whilezeroprevalencewasseenamongblooddonors.A higherseroprevalenceof4.6%wasreportedinthesameregion in1998usingLotQualityAssuranceSampling(LQAS)method, whichidentified25(69.4%)communeswithprevalencehigher than 4.0%.51 _{Aprobandstudyidentifiedaseroprevalenceof} 27.5% among138relativesof32infectedsubjectsand1.4% among142relativesof32controlsubjects.Theannual inci-dencedensitywasthus,reportedtobe6%.50_{Thereislimited} dataontheprevalenceofHTLVinBeninRepublicasfew epi-demiological studies have been carried out, and no recent studyhasbeenconducted.Othervirus typeshavenotbeen reported(Fig.5).

Côted’Ivoire

Only early epidemiological data of HTLV prevalence are available; a cross-sectional serologic survey identified3.5% prevalence of HTLV-1 in the general population. Neonates andchildrenhad1.6%and1.0%prevalence,respectively.The highest prevalence rates were observed in lepers (13.7%), female prostitutes(7.4%)andpatientswithneurologic syn-dromes(5.8%).TheassociationbetweenHTLV-1andleprosy washowever,notascertained;1.9%ofthepregnantwomen were HTLV-1 seropositive.52 _{A previoussurveyon pregnant} women observed1.84% prevalencein urbanand rural Ivo-rian women.53 _{HTLV-1 prevalenceaveraged 1.0–2.7%in the} different regions,54 _{without significant increasein sexually} overexposedgroups.ThereisnoreportofHTLV-2,3and4. Liberia

Anearly epidemiologicalstudy identifiedthe prevalenceof HTLV-1inLiberiatobe1.6%.55_{NofurtherHTLVprevalence}

Table1–ReportsofHTLVPrevalenceinWestAfrica.

Country Authors Publication

year

Cohorttype Sample number HTLV-1% prevalence HTLV-2% prevalence Total% prevalence

Benin Dumasetal.49 _{1991 AHI 2625 1.50 0.00 1.50}

Houinatoetal.50 _{1996 AHI 1642 1.86 0.00 1.86}

Houinatoetal.50 _{1996 BD 1300 0.00 0.00 0.00}

Houinatoetal.51 _{2002 AHI 2340 4.60 0.00 4.60}

BurkinaFaso Collenbergetal.67 _{2006 ANC 498 1.80 0.00 1.80}

Ghana Biggaretal.40 _{1984 AHI 391 3.60 0.00 3.60}

Biggaretal.40 _{1984 AHI 126 4.00 0.00 4.00}

Biggaretal.41 _{1993 AHI 1242 1.29 0.00 1.29}

Laletal.23 _{1994 D/AHI 139}a _29.496a _6.47a _35.966a

Sakodieetal.42 _{2001 BD 3352 0.50 0.00 0.50}

Armahetal.24 _{2006 ANC 960 2.08 0.10 2.19}

Guinea Gessainetal.74 _{1993 BD 1700 1.0 0.00 1.0}

Jeanneletal.75 _{1995 AHI 718 2.23 0.00 2.23}

Guinea-Bissau

Naucleretal.48 _{1992 ANC 272 3.31 0.00 3.31}

Naucleretal.48 _{1992 HP 987 6.70 0.00 6.70}

Naucleretal.48 _{1992 PO 512 3.70 0.00 3.70}

Anderssonetal.25 _{1997 ANC 1231 2.19 0.08 2.27}

Larsenetal.26 _{2000 A 2127 3.60 0.00 3.60}

Ariyoshietal.44 _{2003 AHI 159 9.43 0.00 9.43}

Ariyoshietal.44 _{2003 STD 126 26.19 0.00 26.19}

Zehenderetal.45 _{2008 ANC 427 2.60 0.00 2.60}

Norrgrenetal.76 _{2008 AHI 1050 3.24 0.00 3.24}

vanTienenetal.46 _{2010 V 2770(1990}b_{) 5.20 0.00 5.20}

vanTienenetal.46 _{2010 V 3110(1997}b_{) 5.90 0.00 5.90}

vanTienenetal.46 _{2010 V 2895(2007}b_{) 4.60 0.00 4.60}

Côte d’Ivoire

Denisetal.53 _{1988 ANC 814 1.84 0.00 1.84}

Ouattaraetal.54 _{1989 AHI 594 2.02 0.00 2.02}

Ouattaraetal.54 _{1989 CSW 149 2.68 0.00 2.68}

Verdieretal.52 _{1989 GP 3177 3.50 0.00 3.5}

Verdieretal.52 _{1989 ANC 513 1.95 0.00 1.95}

Verdieretal.52 _{1989 CSW 390 7.44 0.00 7.44}

Verdieretal.52 _{1989 C 364 1.37 0.00 1.37}

Liberia Hunsmannetal.55 _{1984 RP 620 1.60 0.00 1.60}

Mali Denisetal.53 _{1988 ANC 63 0.00 0.00 0.00}

Diarraetal.62 _{2014 BD 799 1.40 0.00 1.40}

Diarraetal.62 _{2014 MP 156 6.40 0.00 6.40}

Niger Denisetal.53 _{1988 ANC 61 1.64 0.00 1.64}

Nigeria Hunsmannetal.55 _{1984 BD 390 2.60 0.00 2.60}

Olaleyeetal.27 _{1994 CSW 60 3.33 3.33 8.33}

Olaleyeetal.27 _{1994 C 1081 0.74 0.46 1.39}

Olaleyeetal.28 _{1995 ANC 364 5.50 3.85 11.54}

Analoetal.36 _{1998 BD 406 0.70 0.00 0.70}

Analoetal.36 _{1998 MI 30 0.00 0.00 0.00}

Olaleyeetal.29 _{1999 AHI 460 4.35 1.09 5.43}

Olaleyeetal.29 _{1999 C 476 1.05 0.00 1.05}

ForbiandOdetunde33 _{2007 CSW 166 22.9 0.00 22.9}

ForbiandOdetunde33 _{2007 ANC 120 16.7 0.00 16.7}

ForbiandOdetunde33 _{2007 HSS 78 5.1 0.00 5.1}

TerryAllietal.31 _{2011 BD 372 3.6 0.00 3.6}

Durojaiyeetal.32 _{2014 AHI 26 0.00 0.00 0.00}

Okoyeetal.1 _{2014 ANC 200 0.50 0.00 0.50}

Okoyeetal.37 _{2015 BD 300 0.00 0.00 0.00}

Oladipoetal.34 _{2015 BD 300 25.8 0.00 25.8}

Opaleyeetal.35 _{2016 ANC 182 24.2 0.00 24.2}

Ma’anetal.38 _{2016 BD 500 0.00 0.00 0.00}

Mangaetal.39 _{2016 BD 355 0.00 0.00 0.00}

Senegal Hunsmannetal.55 _{1984 RP 993 1.20 0.00 1.20}

–Table1(Continued)

Country Authors Publication

year

Cohorttype Sample number HTLV-1% prevalence HTLV-2% prevalence Total% prevalence Kaplanetal.74 _{1994 TB 197 1.50 0.00 1.50} Diopetal.30 _{2006 BD 4900 0.14 0.02 0.16}

TheGambia Pepinetal.68 _{1991 CSW 355 10.40 0.00 10.40}

DelMistroetal.69 _{1994 AHI 909 1.21 0.00 1.21}

DelMistroetal.69 _{1994 C 916 0.11 0.00 0.11}

Togo Denisetal.53 _{1988 ANC 565 1.40 0.00 1.40}

Balogouetal.75 _{2000 AHI 1717 1.20 0.00 1.20}

Balogouetal.75 _{2000 NP 828 1.80 0.00 1.80}

Balogouetal.75 _{2000 NNP 244 1.60 0.00 1.60} Key:V,variable;C,children;A,adults;AHI,apparentlyhealthyindividuals;CSW,commercialsexworkers;MI,malignantindividuals;BD,blood donors;ANC,antenatalcare(pregnant)women;HSS,highschoolstudents;PO,policeofficers;STD,sexuallytransmitteddiseaseinfected individuals;D,individualsinfectedwithdisease;MP,mistransfusedpatients;GP,generalpopulation;RP,ruralpopulation;HP,hospitalized patients;NP,neurologicalpatients;NNP,non-neurologicalpatients;TB,patientswithtuberculosis.

a _{Previouslyreactivetopreliminaryassay.} b _{Yearofsurvey.}

studieshavebeencarriedoutinLiberia.However,astudy car-riedoutonSpanishimmigrantsidentifiedHTLV-2inaLiberian native.56 _{TherewasarecentreportofHTLV-1seropositivity} inapatientwithtypicalHAM/TSPwhowasborninLiberia butnowresidentintheUnitedStates.57_{Thisisindicativethat} HTLV-1and2arestillexistentinLiberia(Fig.5).

SierraLeone

In a hospital sample in Sierra Leone, a patient was pre-sumed to have HTLV-1 uveitis.58 _{Cosmopolitan strains of} HTLV-1fromAmerica,Caribbean,Japan,Polynesiaand Equa-torialDRCongoaresaidtohavedivergedfrom(Indo-Malay) AsianSTLV-1strainsfromIndianmacaques(Macacamulatta)to Africanbaboons(P.hamadryasandPapiocynocephalus),before divergingfromAfricanSTLV-1strainsofwhichstrainsfrom SierraLeoneancommonchimpanzee,CH(Pantroglodytes)are among.59_{Despitethese,therearenoavailabledataonHTLV} epidemiologyintheSierraLeoneanpopulation.

Mali

HTLV-1 infection of Malian Origin hasbeen documented60 and cases of adult T-cell leukemia/lymphoma (ATLL) have beencharacterizedamongMalianpatients.61_Anearlystudy observed zero prevalence in a small cohort of pregnant women.53_{Co-infectionswithHIV-2andStrongyloidesstercoralis} areplausible.Asurveycarriedoutamongblooddonorsand mistransfusedpatientsyielded1.4%(Table1)and6.4% HTLV-1prevalence,respectively.62_{HTLV-2, 3and 4havenotbeen} reported.

NigerRepublic

Inanearlystudy,1.64%prevalenceratewasseenamong preg-nantwomenfromruralarea.53_{Develouxetal.}63_identifieda caseoftropicalspasticparaparesisassociatedwithHTLV-1in NigerRepublic.NorecentHTLV epidemiologicalsurveyhas beencarriedoutintheNigerienpopulation.However,a 55-yearoldmaledonorofNigerienoriginwasfoundtobeHTLV-1 positiveinanIsraelistudy.64_{OtherHTLVtypeshavenotbeen} reported(Fig.5).

Guinea

Only two studies have reported the prevalence of HTLV-1 (Table1).Nocurrentprevalencedataisavailable.Therehas beennoreportoftheotherthreeHTLVtypes.

CaboVerde

Zanellaetal.65_{identifiedcasesofHTLV-1/HIV-2co-infectionin} CaboVerde.Theprevalenceratesofinfectionandco-infection werehowever,notdefined.Fulllengthgenome characteriza-tionoftheidentifiedHTLV-1isolatesrevealedthemtobelong totheHTLV-1aDsubgroup.66_{Nootherstudy isavailableon} HTLVpresenceand/orprevalenceintheCaboVerdean popu-lation.

BurkinaFaso

TheonlyreportonHTLVprevalenceisthestudyconducted in2006byCollenbergetal.67_{whoalsoidentifiedcasesof} co-infectionamongthestudypopulation(Table1).

TheGambia

Prevalenceratesof0–10.4%forHTLV-1havebeendescribedin TheGambia68,69_{(Table1).HTLVshavenotbeenreportedlater} than1994.

Senegal

SenegalisestimatedtohaveHTLV-1prevalenceof143/100,000 inhabitants30,55_{(Table1).Kaplanetal.}70_{identified1.5%HTLV-1} co-infectionwithHIVamonghospitalpatientswiththe diag-nosis ofpulmonarytuberculosis. Seroprevalence ofHTLV-2 was0.02%amongblooddonors30_{inDakar.HTLV-1aD(North} Africansubgroup)istheprevalentsubgroupinSenegal. HTLV-3and4havenotbeenisolated.

Togo

The prevalence rate of HTLV-1 in Togo falls between 1.2% and1.8%50,53,71_{(Table1).OthertypesofHTLVhavenotbeen} reported.

AvailabledatashowthatWestAfricafallswithinregions withmoderatetohighHTLV-1prevalence.Nigeristheonly countryinWestAfricawithlowprevalenceofHTLV-1.There

3000 km (equat.) 2000 mi (equat.) HTLV 1 Spread HTLV 2 Spread HTLV 1 HTLV 2 HTLV 3 HTLV 4

Fig.4–GlobaldistributionandspreadofHTLVs. are few reports of HTLV-2. The co-infection of HTLV with

othersexuallytransmittedviruseslikeHIV-1orHIV-2, hepati-tisviruses,andhumanpapillomavirus(HPV)inmostplacesis largelyunknownastherearesporadicrecordsofincidence.14 AlthoughHTLV-3and4havenotbeenreported,thereisriskof transmissionofthevirustypessincetherearereportsoftheir presenceinCameroon,aneighbouringcountry.3,4

Routine

screening

for

HTLVs

ThescreeningofblooddonorsforHTLV-1/2infectionalongside othermandatorytestsbeforedonationhasbeenmandated inmany endemiccountries –Asia –China, Japan,Taiwan; America:Argentina,Brazil,Canada,Colombia,FrenchWest Indies,Jamaica,Peru,USA,andVenezuela;Australia;Europe: NewZealand,Sweden,UK,Uruguay,France,Greece,Ireland, Netherlands,Portugal,Romania,Denmark,Finland,and Nor-way.MiddleEast: Israel,Iran,andSaudiArabia.72 _However, routinescreeninganddiagnosisofHTLV-1/2infectionamong blooddonorsinWestAfricaandotherendemicpartsofAfrica, israrelypracticed,despitethefactthattheseregionsareof moderatetohighendemicity.

HTLV-3

and

HTLV-4

Twonewviruses,geneticallyrelatedtoHTLV-1and2(although more related to their STLV counterparts), were discovered in the same geographical region, the rainforest part of Southern Cameroon, Central Africa.3,4 _{On isolation from} asymptomatic pygmies and Bantus, they were subjected

toenzymeimmunoassay(EIA) and Westernblotting which yielded indeterminate results to bothHTLV-1 and 2.Their proviruseswerethendetectedusingaseriesofPCRprimers designed to amplify all known HTLVs and STLVs.3,4 _The infectedindividualswereeitherhunters,orlivinginthe rain-forestregion(Fig.4),characterizedbyexistenceofnon-human primateshighlyinfectedwithSTLVs.Itistherefore,notout ofplace to suggest that theymay havediverged via inter-speciestransmissionfromnon-humanprimatestohumans. Therelatednesstootherdeltavirusesledtotheirplacementin thesamegenusandfamily,andthedesignationofthenames HTLV-3andHTLV-4.

The tax gene of HTLV-3, like HTLV-1, contains a PDZ binding motif while HTLV-4 does not. The motif binds to PDZdomainandpromotesvirus-mediatedT-cellproliferation

invitroandpersistenceinvivo.PDZ(postsynapticdensity95, PSD-85;Discslarge,Dlg;Zonulaoccludens-1,ZO-1)domains are modularproteininteraction domains–formerlyknown as Discs-large homology regions (DHRs) or GLGF repeats, afteraconservedGly-Leu-Gly-Phesequencefoundwithinthe domain – that playa role inprotein targetingand protein complex assembly.73 _{ThepresenceofHTLV-3and4viruses} in Cameroon, though notassociated with any diseases, is depictiveoftheirpossiblepresenceinotherWestandCentral Africancountries.

Are

indeterminate

HTLV

results

in

West

Africa

an

insight

to

a

new

virus

type?

There are several reports of indeterminate WB patterns resultingfromHTLVreactivesera/plasmasamplesinAfrica.

300 km 200 mi

HTLV 1 HTLV 2

Fig.5–DistributionofHTLV-1and2inWestAfrica.

Researchershavesuggestedcross-reactivitywithantigenof

Plasmodiumfalciparum39 _{andofvariousinfectiousagents,as} well as low proviral load or co-infection with other infec-tiousagentslikeHIV.However,mostoftheseindeterminate resultsinapparentlyhealthy individuals arenotHLTV-3or 4,uponsubjectiontofurtherconfirmatoryassays.Persistent increasedrateofindeterminateresults,whicharenot HTLV-3orHTLV-4uponsubjectiontofurtherconfirmatoryassays, oughttobelookedinto.ItshouldberecalledthatHIV-1and 2 (previously named HTLV-3 and 4) were initially grouped togetherwithHTLV-1and2,andwere onlyregroupedafter further research. Therefore, further investigative research on these indeterminate cases is warranted, as there is a possibility that the indeterminate WB resultsencountered withEIA/PAreactive samplescouldbe newHTLV-1, 2,3or 4 subtypes, yet-to-be discovered HTLV type or an entirely newundiscovered infectious agents withsimilar reactivity toEIA.

Conclusion

AlthoughtheprevalencerateofHTLVintarget risk popula-tionsisusefulepidemiologicaldata,theymaynotgiveatrue representationforaccurateestimationofHTLVinfectionsin WestAfrica,astheyaremostlyrestrictedtovisitationsofstudy participantstothehospitals(hospital–basedstudies).Most

Africansengage inself-medication, astheydonotvisitthe hospitalsuntiltheypresentwithseveresymptoms.Givingthe longlatencyofthevirus,aswellasthefactthatdiagnostic and/orroutinescreeningishithertonotmandatory,thereal prevalenceratesofHTLVsmaybehigherthan thosefound inthereviewedstudies.Itshould benotedthatprevalence datafrompopulation-basedstudieshaveatrendtobemore accurateoncetheyareconsideredhealthyindividuals.West AfricanlacksrecentepidemiologicaldataonHTLVprevalence. Nation-widegeneralpopulationbasedstudiescapturingthe communities(apparently healthypopulation)should there-forebeconsidered,soastoascertainthetrueprevalenceof thesevirustypes.Furthermore,thesignificantlyhighrateof HTLVindeterminateWBserologicalpatternsinAfrican stud-iescallsforconcern.Althoughcross-reactivitywithantigens ofsomeotherinfectiousagentshavebeenhypothesized,there arepossibilitiesthatsuchreactionscouldberesultantfrom yet-to-bediscoveredHTLV(sub)typesoranentirelyunknown virus/infectious agent. Itisimperative thatroutine screen-ingforHTLVsbemandatedinWestAfrica,especiallyinthe healthcarecentersandhospitalsthatengageinblood dona-tionand/ortransfusion,sinceWestAfricaisaregionofhigh endemicity ofHTLV-1 and 2. Itshould benoted that West Africa isat risk ofHTLV-3 and 4transmission and subse-quentendemicity, giventhe presenceofthevirus typesin Cameroon,aneighbouringcountrytoNigeria,aWestAfrican country.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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n

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