w w w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Original
article
HLA-B*14
allele
predicts
HIV-1
mother-to-child-transmission,
in
Salvador,
Brazil
Juan
Manuel
Cubillos
Angulo
a,b,
Taryn
Ariadna
Castro
Cuesta
b,
Eliane
Pereira
Menezes
b,
Celia
Pedroso
a,
Carlos
Brites
a,∗aLaboratóriodePesquisaemInfectologia,Salvador,BA,Brazil
bUniversidadeFederaldaBahia,EscoladeMedicinaSalvador,ComplexoHospitalarProf.EdgardSantos,Salvador,BA,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received11December2018 Accepted25April2019 Availableonline18May2019
Keywords:
Mothertochildtransmission HIV
HLA-B
a
b
s
t
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a
c
t
Background:ClassIhumanleukocyteantigens,especiallythemoleculesencodedattheB locus(HLA-B),areassociatedwithAIDSprogressionrisk.DifferentgroupsofHLA-Balleles havebeenassociatedtoaprotectiveeffectorincreasingsusceptibilitytoHIVinfectionand areexpressedfromtheearlieststagesofgestation.
Objective:TheaimofthisstudywastoevaluatewhichvariantsofHLA-Bareassociatedwith theriskofHIVverticaltransmissionininfectedpregnantwomenandintheiroffspring,in areferralcenterinSalvadorBahia.
Methods:WeperformedHLA-Bgenotypingin52HIV-infectedmothersandtheirchildren exposed toHIV-1 duringpregnancy(N=65)inSalvador,Brazil.WecomparedtheHLA-B alleles frequencyinmothers,uninfectedandinfectedchildren,accordingtotheuseof antiretroviralprophylaxis.
Results:Absence of antiretroviralantenataland postnatalprophylaxiswas significantly associatedwithverticaltransmissionofHIV-1 (p=<0.01,andp=<0.01respectively). Fre-quencyofHLA-B*14(29.2%,p=0.002),HLA-B*18(16.7%,p=0.04)orHLA-B*14:1(20.8%,p=0.01) allelessubgroupsweresignificantlyhigherinHIV-1infectedchildrenandpersisted (HLA-B*14, p=0.04) even after adjusting foruse of antiretroviral prophylaxis. Nosignificant differenceinexpressionofHLA-Balleleswasobservedamongmotherswhotransmitted theviruscomparedtothosewhodidnot.
Conclusions: ExpressionofHLA-B*14 allele in childrenexposed toHIV-1 is predictiveof verticaltransmissionandreinforcestheimportantroleofgeneticsinmother-to-child trans-mission.
©2019PublishedbyElsevierEspa ˜na,S.L.U.onbehalfofSociedadeBrasileirade Infectologia.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mailaddress:crbrites@gmail.com(C.Brites).
https://doi.org/10.1016/j.bjid.2019.04.009
1413-8670/©2019PublishedbyElsevierEspa ˜na,S.L.U.onbehalfofSociedadeBrasileiradeInfectologia.Thisisanopenaccessarticle undertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
In2016therewere36.7millionpeoplelivingwithHIV/AIDS (PLHIV)including2.1millionofchildrenunder15yearsofage.1
Inabsenceofantiretroviralprophylaxis, 30–40%ofchildren borntoHIV-infectedmothersbecomeinfected,eitherduring pregnancy(5–10%),delivery(15%),orthrough breastfeeding (15%).2
Theassociationbetweenhumanleucocytesantigen sys-tem(HLA)classIandHIVinfectionisalreadyknown.3TheHLA
systemispartofthemajorhistocompatibilitycomplex(MHC) thatmodulatesthehostimmuneresponse.ClassIgenesare expressedbymostsomaticcells,4 and arecharacterizedby
alargenumberofalleles(n=12,893,March,2018,IMGT-HLA). Mostvariantsarelocatedinthepeptide-bindingregion,which confersanevolutionadvantageinthecontrolandprogression ofinfections.5
TheHLA-BallelehasbeenassociatedwithHIVinfection progression,incomparisontootherHLAalleles.Thisislikely becausethe largenumber ofalleles3 (4950 byMarch, 2018,
IMGT-HLA)anditsphysiologicalinfluenceonCD8+T lympho-cytes’activity.6Fetalproteinsareexpressedearlyinembryonic
development,inthefirsttrimesterofpregnancy.ClassicalHLA classIproteinsareexpressedinallnon-trophoblasticcellsof motherandfetus.7
Theassociation between the presenceofcertain HLA-B antigensandthelikelihoodofmother-to-child-transmission (MTCT)hasbeenreportedbyseveralauthors,asprotectiveor predictiveofhighersusceptibilitytoHIVinfection.8–12 Such
antigensareexpressedearlyinthegestationalperiodandcan influenceprogressiontoAIDS.
TheimportantroleofHLA-B*57allelicgroupsagainstHIV progression inadults is well documented.13–16 Similarly, a
strongassociationbetweentheseallelesandaslow progres-siontoAIDSinHIV-infectedchildrenhavebeenreportedin MTCTstudies.17–19Ontheotherhand,theavailableevidence
suggest that the expression ofthe allelic groups HLA-B*35 is linked to faster progression to AIDS and to higher risk of MTCT2,3 than in individuals not expressing such HLA
alleles.20,21
ReportsonthefrequencyofHLA-Bpolymorphismsin HIV-infectedmothers and their offspring are scarce.Our study aimedtoevaluatethefrequencydistributionofHLA-Balleles inHIV-infectedmothersandtheirchildren,and todefineif therewas any association betweenHLA-B alleles polymor-phismsandthelikelihoodofMTCT,inSalvador,Brazil.
Methods
Weconductedacross-sectionalstudytoevaluatethevariants ofHLA-B allelesinHIV-infectedwomenandtheir offspring exposedtoHIVinfectionduringpregnancy.Theparticipants werefollowedattheHospitalUniversitárioProfessorEdgard Santos(HUPES)HIVoutpatientclinics,inSalvador,Brazil,from April2017toFebruary2018.HIV-infectedwomenolderthan 18years,andtheirexposedchildrenwereincluded.Thestudy wasapprovedbytheEthicsinResearchCommitteeof Mater-nidade Climériode Oliveira,Universidade FederaldaBahia
(number 1035.826,April2015).Thestudywas conductedin accordancewithGoodClinicalPractices,andtheethics prin-ciplesoftheDeclarationofHelsinki.
Afterwrittenconsenttoparticipateinthestudy,included women were interviewed on demographics, HIVdiagnosis, route ofHIVtransmission, andgestational period.Data on HIV-1 plasma viral load and CD4+/CD8+ cell count were retrievedfromBrazilianNationalDatabaseonHIVviralload and lymphocytes count (SISCEL). Information on perinatal prophylaxiswasabstractedfrommedicalrecords.
BloodsampleswerecollectedintubescontainingEDTAto performHLAallelesevaluation.Briefly,DNAextractionwas performedbyPureGenomic DNAmini kit(Invitrogen).The concentrationofgenomicDNAwasmeasuredbyaDNA quan-tifier,tokeepitbetween50and280ng/mL.Alllaboratorytests were performedat the Laboratório de Pesquisasem Infec-tologia(LAPI),andImunogeneticsLaboratory,bothlocatedat HUPES.
HLA genotyping was performed by using LABType SSO HLA-B Locus (One Lambda), according to manufacturer’s instructions.Briefly,LABTypeuseaLuminexplatformto per-forminvertedsequencespecificoligonucleotides(SSODNA) typing.Initially,thetargetDNAwasamplifiedbyPCRusing a specific primer for the target group. The PCR productis biotinylatedtoallowdetectionbyastreptavidin-conjugated R-phicoeritrin(SAPE).ThePCRproductwasthendenatured andhybridizedwithDNAcomplementaryprobesconjugated withfluorescentmicrospheres.Aflowanalyzer(LABScan100) readsthefluorescenceintensityofphycoeritrinineach micro-sphere.HLAtypingwasdefinedbycomparisonoftheobtained reactionpatternwiththoseassociatedwithHLAsequences alreadypublished.
Statistical
analysis
The categoricalvariables were described byfrequency dis-tribution and percentages. Comparisonbetween frequency groupsandsubgroupsofHLA-Ballelesdetectedinmothers andchildrenwasperformedbyPearson-correctedchi-square.
pvalues<0.05wereconsideredsignificant.Homozigousalleles orHLA-B subtypeswerereadasasingleone,toavoiddata duplicity.
Thefrequencyofchildren’sallelessignificantlyassociated withHIVtransmissionwasfurtheranalyzedbybinary logis-ticregression.Continuousvariablesweredescribedbycentral tendencymeasures,medianandinterquartileintervals.
Allelic frequencies were calculated by alleles counting method. Genotype deviation and Hardy–Weinberg balance werecheckedformothersandchildrenbyusingthesoftware Genepopversion4.2.22Allanalyseswereperformedwiththe
statisticalpackageSPSS,version21.ThesoftwareJMPversion 11wasusedforgraphicanalysisofallelicfrequencies.
Results
Atotalof65bloodsamplesofchildrenexposedtoHIV-1during pregnancy,24oftheminfectedbytheviruswereevaluated.In addition,52samplesofmothers,14ofthemtransmittedHIVto
Table1–Socio-demographicandclinicalcharacteristicsofHIV-1-infectedmothersenrolledinthestudyaccordingto MTCTstatus.
Transmitters(n=14)a Nontransmitters(n=38)a p-Value
EthnicityN(%) 0.5 White 0 1(2.6) Black 1(20.0) 17(44.7) Brown 4(80.0) 20(52.6) MaritalstatusN(%) 0.14 Single 3(60.0) 16(42.1) Married 2(40.0) 4(10.5) Widowed 0 1(2.6) Unmarried/cohabitationa 0 17(44.7) EducationN(%) 0.11 <5years 1(20.0) 13(34.2) 5–8years 0 7(18.4) 8–11years 1(20) 4(10.5) 11years 2(40) 9(23.7) Highereducation 0 4(9.3) Illiterate 0 1(2.6) Others 1(20.0) 0 IncomeN(%) 0.88
Lessthan1minimumwage 2(40.0) 13(34.2)
1minimumwages 2(40.0) 20(52.6) 2minimumwages 1(20.0) 4(10.5) 2–3minimumwages 0 1(2.6) EmploymentN(%) 0.81 Housewife 4(80.0) 24(63.2) Retired 0 1(2.6) Student 0 5(13.2) Others 1(20.0) 8(21.1) SmokingN(%) 0.11 Smoker 0 4(10.5) Ex-smoker 3(60.0) 7(18.4) Non-smoker 2(40.0) 27(71.1)
IllicitdruguseN(%) 0.82
Marijuana 0 3(7.9)
Cocaine 0 3(7.9)
Non-illicitdruguse 5(100) 32(84.2)
AlcoholuseN(%) 0.35
Occasional 2(40.0) 7(18.4)
Daily 0 3(7.9)
Discontinueduseinpregnancy 0 12(31.6)
Sober 3(60.0) 16(42.1) ComorbiditiesN(%) 0.29 Cardiopathy 0 1(2.6) Tuberculosis 1(20.0) 2(5.3) Others 2(40.0) 6(15.8) Yes 2(40.0) 29(76.3)
MotheruseofprophylaxisagainstHIVN(%) 0.007
Yes 11(50.0) 32(84.2)
Not 11(50.0) 6(15.8)
DeliverymodeN(%)
Cesareansection 4(80.0) 35(92.1) 0.446
–Table1(Continued)
Transmitters(n=14)a Nontransmitters(n=38)a p-Value
PreviousabortionN(%) Spontaneous 2(50.0) 4(10.5) 0.009 Induced 1(25.0) 1(2.6) Nonabortion 1(25.0) 33(86.8) GestationalageN(%) Term 5(100.0) 34(89.5) 0.446 Preterm 0 4(10.5)
a Notethateachsubcategorymayhaveavalueofnsmallerbyincompletedatainthequestionnaire.
theirchildrenwerealsoevaluated.Thediscrepancybetween thenumberofmothersandchildrenisduetothreepairsof twinsanddeathofthreemothersbeforesamplescollection.
Table1showsthesocio-demographicandclinical character-isticsoftheincludedmothers.
Amongthe38mothersthatdidnottransmitHIV-1totheir children,36(94.7%)receivedantenatalantiretroviral prophy-laxis,comparedtoonly13 (54.2%)out 24 motherswho did transmitHIV-1totheirchildren(p=<0.01).Furthermore,the 38motherswhodidnottransmitHIV-1totheirchildren,33 (86.8%)received MTCT postnatal prophylaxis, compared to only57.9%(11/19)amongthosewhotransmittedHIV-1totheir children(p=<0.01).Five (20.8%)transmitting mothers were losttofollowup.
HIV-1infectionwasconfirmedin24/65(37%)ofexposed children,asshowninTable2.TheproportionofHIVinfected childrenwas similar formales (11/30)and females (13/35) (Table3).
Asexpected,therewasaclearassociationbetweenuseof antiretroviralprophylaxisinthefirstfour weeksoflifeand lowerriskofHIVinfectionamongexposedchildren:39(95%) uninfectedchildrenreceivedperi-partumprophylaxis, com-paredtoonly13(54%)infectedchildren(p<0.001).
WedidnotfindsignificantdeviationfromHardy–Weinberg equilibriumamong thechildren. However,a deviationwas detectedamong mothers, probably as a consequence of a selectionbias(allmotherswereinfectedbyHIV-1).
There was a significant association between frequency ofHLA-B*14(p=0.002)and HLA-B*18(p=0.04)allelicgroups and HIV infection among exposed children, as shown in Table 2. In infected children who received antiretro-viral prophylaxis, the association between HLA-B*14 and MTCT remained significant (Table 4, p=0.04). MTCT of HIV was also associated to the expression of HLA-B*14:01 subgroup (Table 2, p=0.02). On the other hand, we did not detect any significant association between HIV trans-mission and expression of HLA-B*41 or HLA-B*52 alleles.
Figs.1and 2display thealleles’frequencyin theincluded children.
Amongmothers,thefrequenciesoftheevaluatedalleles were similar,regardlessMTCT. However,therewasa trend (p=0.06) towardassociation betweenHLA-B*44allele and a lowerchanceofHIVtransmission(Table2).Figs.3and4 sum-marizetheallelesfrequenciesinmothers.Thefrequencyof HLA-B*44:02subtypewassimilaramongmotherswhoeither transmittedHIVtotheirchildrenornot.HLA-B*57alleleand
HLA-B*57:01subgroupswerenotfoundamongmotherswho transmittedHIV.Theoverallfrequencyofthesealleleswas3.1 and2.3%,respectively.
ExpressionofHLA-B*14allelewaspredictive(p=<0.01)of HIV-1 MTCT.Logisticregression controllingforantenatalas wellaspostnatalprophylaxis(Table5)showedpersistent asso-ciationbetweenfrequencyofHLA-B*14andincreasedriskof HIV-1MTCT,incomparisonwithuninfectedchildren(OR29.0; 95%IC2.28–368.72).
Discussion
HIV-1MTCTdependsonthemagnitudeofmaternalHIV-1viral load,andcompleximmunologicalandgeneticmechanisms. AsignificantassociationbetweenriskofMTCTand expres-sionofHLA-B*14inchildreninfectedbyMTCTwasdetected inthisstudy.TheassociationwithMTCTremainedsignificant afteradjustingforantiretroviralprophylaxis,indicatingthat geneticcharacteristicsplayamajorroleinthepathogenesis ofHIV-1MTCT.AmongHIV-infectedchildrenborntomothers whoreceivedantiretroviralprophylaxis,46.2%expressed HLA-B*14allele,againstonlyoneinfectedchildbornfrommother whodidnotreceivedprophylaxis.
ThefrequenciesofHLA-B*14andB*18inthegeneral pop-ulation inBahia are 5.6%and 4.3%, respectively, according to theNational Registry ofBone MarrowDonors (REDOME, available http://www.allelefrequencies.net/hla6006a.asp). In ourstudy,thefrequencyofHLA-B*14allelewas29.2%among HIV-infectedchildren,whereasitwasonly2.4%among unin-fectedchildren(Table2).Thisreinforcetheconsistencyofour findings,and demonstratesthe strong associationbetween HLA-B*14alleleandHIV-1MTCT.
PreviousstudieshavesuggestedthatHLA-B*14couldplay an important role in HIV pathogenesis. Winchester et al. detectedahigherfrequencyofHLA-B*14inHIV-infected chil-dren, compared to uninfected ones.21 On the other hand,
Paximadisetal.foundahigherfrequencyofHLA-B*14among motherswhotransmittedHIVtotheiroffspringthaninthose whodidnot,reinforcingtheassociationbetweenthatallele expression and MTCT.23 Other findings suggest that
HLA-B*14isassociatedwithhighlevelsofviremiainHIV-infected individuals,andhigherreplicativecapacityinmothers.6,20In
addition,wedetectedahigherfrequency(16.7%)ofHLA-B*18 inHIV-infectedchildrenthanthatobservedinthegeneral pop-ulationofSalvador(2.4%,p=0.04).
Table2–FrequencyofHLA-Ballelicgroupsandsubgroupspotentiallyassociatedwithmother-to-childtransmissionof HIV-1inexposedchildren.
Alleles HIV p-Value OR
(95%IC) Positive (n=24) Negative (n=41) B7a 3(12.5) 5(12.2) 0.97 1.0(0.2–4.7) B14 7(29.2) 1(2.4) 0.002 16.5(1.9–144.4) B15a 4(16.7) 11(26.8) 0.348 0.5(0.2–2.0) B18 4(16.7) 1(2.4) 0.04 8(0.8–76.4) B35 4(16.7) 8(19.5) 0.78 0.8(0.2–3.1) B41 0 4(9.8) 0.11 – B42 2(8.3) 5(12.2) 0.62 0.7(0.1–3.7) B44 5(20.8) 6(14.6) 0.52 1.5(0.4–5.7) B52 0 4(9.8) 0.11 – B53 2(8.3) 5(12.2) 0.6 0.7(0.1–3.7) B57 1(4.2) 3(7.3) 0.6 0.6(0.1–5.6) Subgroups B07:02a 2(8.3) 4(9.8) 0.85 0.8(0.1–4.9) B14:01 5(20.8) 1(2.4) 0.01 10.5(1.2–96.5) B15:03a 1(4.2) 7(17.1) 0.13 0.2(0.02–1.8) B35:01 3(12.5) 6(14.6) 0.81 0.8(0.2–3.7) B44:02 3(12.5) 2(4.9) 0.27 2.8(0.4–18.0) B44:03 2(8.3) 4(9.8) 0.85 0.8(0.1–4.9) B51:01 4(16.7) 5(12.2) 0.61 1.4(0.3–5.9) B53:01 2(8.3) 5(12.2) 0.63 0.7(0.1–3.6)
a Presenceofhomozygotesinthesample.
Table3–FrequencyofHLA-Ballelicgroupsandsubgroupspotentiallyassociatedwithmother-to-childtransmissionof HIV-1ininfectedmothers.
Alleles Transmitters (n=14) Non-transmitters (n=38) p-Value OR (95%IC) B15a 3(21.4) 14(34.2) 0.38 0.5(0.1–2.2) B35 2(14.3) 6(15.8) 0.89 0.9(0.2–5.0) B44a 7(50) 9(23.7) 0.06 3.2(0.9–11.6) B57 0 4(10.5) 0.21 – Subgroups B15:03a 3(21.4) 5(13.2) 0.46 1.8(0.37–8.8) B44:02 4(28.6) 4(10.5) 0.11 3.4(0.6–12.7) B44:03 3(21.4) 5(13.2) 0.46 1.8(0.4–8.8) B57:01 0 3(7.9) 0.28 –
a Presenceofhomozygotesinthesample.
Table4–FrequencyofHLA-BallelicgroupspotentiallyassociatedwithHIVmother-to-childtransmissioninHIV-1 infectedchildrenwhoreceivedantiretroviralprophylaxis.
Alleles Prophylaxis p-Value OR (95%IC) Yes (n=13) Not (n=11) B14 6(46.2) 1(9.1) 0.04 8.6(0.8–87.8) B15 2(15.4) 2(18.2) 0.85 0.81(0.1–7.0) B18 2(15.4) 2(18.2) 0.85 0.82(0.1–7.0) B42 1(7.7) 1(9.1) 0.90 0.83(0.1–15.1)
Winchesteretal.alsodetectedahigherfrequencyof HLA-B*44alleleintransmittingmothers,andahigherriskofMTCT amongAfro-Americansor Hispanicwomen.21 In ourstudy,
therewasahigherfrequencyofHLA-B*44amongtransmitting
than non-transmittingmothers,but itwas onlymarginally significant,probablyduetothesmallsamplesize.Similarly, we did not detect expression of HLA-B*57 allele in trans-mittingmothers,reinforcingitspotentiallyprotectiveeffect
0.0 2.0 4.0 6.0 8.0 10.0 12.0 B07 B08 B13 B14 B15 B18 B27 B35 B37 B38 B39 B40 B41 B42 B44 B45 B49 B50 B51 B52 B53 B57 B58 B81 HIV-1 positive HI V-1 negative HLA-B alleles
Fig.1– FrequencyofHLA-BallelicgroupsinchildrenexposedtoHIV-1.
0.0 2.5 5.0 7.5 10.0 12.5 15.0 HLA-B alleles B13 B14 B15 B18 B27 B35 B37 B38 B39 B40 B41 B42 B44 B45 B50 B51 B52 B53 B57 B58 B7 B72 B8 B81
HIV -1 non transmitters
HIV -1 transmitters
Fig.2–FrequencyofHLA-BallelicsubgroupsinchildrenexposedtoHIV-1.
HIV -1 negativ
e
HIV -1 positiv
e
HLA-B alleles subgroups
B*07:02 B*07:05 B*08:01 B*13:02 B*14:01 B*14:02 B*15:03 B*15:04 B*15:08 B*15:10 B*15:17 B*15:31 B*18:01 B*27:03 B*35:01 B*35:03 B*35:05 B*35:20 B*37:01 B*38:01 B*39:01 B*39:09 B*40:02 B*41:01 B*41:02 B*42:01 B*44:02 B*44:03 B*45:01 B*50:01 B*51:01 B*51:04 B*52:01 B*53:01 B*57:02 B*57:03 B*58:01 B*58:02 B*81:01 B*81:03 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0
Fig.3–FrequencyofHLA-BallelicgroupsinHIV-1positivemothers.
against MTCT, because decreased replicative capacity has beenattributedtoits expression,asdescribedbyAdland.20
However,thedifferencedidnotreachstatisticalsignificance. Themainlimitationofourstudyisthesmallsamplesize, whichprobablyreducedstatisticalpowertodetect relevant
differences in expression of alleles HLA-B*44 and B*57, as previouslydemonstratedinotherstudies.However,the signif-icantassociationbetweenMTCTandHLA-B*14allele expres-sionreinforcestheimportanceofgeneticcharacteristicsand MTCT ofHIV-1.Largerprospectivestudiescanincreaseour
0.0 1.0 2.0 3.0 4.0 5.0 6.0 B*07:02 B*07:05 B*08:01 B*13:02 B*14:01 B*14:02 B*15:03 B*15:04 B*15:05 B*15:07 B*15:10 B*15:17 B*15:20 B*15:31 B*18:01 B*27:03 B*35:01 B*35:03 B*35:20 B*37:01 B*38:01 B*39:01 B*39:06 B*40:01 B*40:02 B*40:04 B*41:01 B*41:02 B*42:01 B*44:02 B*44:03 B*44:10 B*45:01 B*50:01 B*50:02 B*51:01 B*52:01 B*53:01 B*57:01 B*57:02 B*58:01 B*58:02 B*81:01
HLA-B alleles subgroups
HIV -1 non transmitters
HIV -1 transmitters
Fig.4–FrequencyofHLA-BallelicsubgroupsinHIV-1positivemothers.
Table5–AdjustedORofallelesexpressionassociatedtoHIV-1mother-to-childtransmissioninexposedchildrenafter binarylogisticregression.
Alleles ORcrude ORadjusted 95%IC p-Value
B14 16.5 18.1 (2.05–166.33) 0.01 B15 0.5 1.4 (0.32–6.13) 0.66 B18 8 10.2 (0.96–107.9) 0.06 B44 1.5 2.1 (0.48–9.14) 0.33
understanding of the role of genetic mechanisms on HIV transmissionandpathogeny.Ourfindingsdemonstratethat MTCTisstronglyassociatedwithHLA-B*14expressionand canpredictthelikelihoodofHIV-1MTCT,probablyasa conse-quenceofaninadequateimmuneresponsetoHIVinfection.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
WethankMarcosNeriandAugustoHoraforbloodcollection andMariaBelenArriagaforhersupportinstatisticalanalyses. ThisstudywassupportedbyagrantfromFundac¸ãoBahiana deinfectologia.
r
e
f
e
r
e
n
c
e
s
1. UNAIDS.UNAIDSData2017.JtUnitedNationsProgram HIV/AIDS;2017.p.1–248.
2. PrendergastAJ,KlenermanP,GoulderPJR.Theimpactof differentialantiviralimmunityinchildrenandadults.Nat RevImmunol.2012;12:636–48.
3. MartinMP,CarringtonM.ImmunogeneticsofHIVdisease. ImmunolRev.2013;254:245–64.
4. JanKleinAS.TheHLAsystem.Nejm.2000;343:702–9. 5. SidneyJ,PetersB,FrahmN,BranderC,SetteA.HLAclassI
supertypes:arevisedandupdatedclassification.BMC Immunol.2008;9:1–15.
6.KiepielaP,LeslieAJ,HoneyborneI,etal.Dominantinfluence ofHLA-Binmediatingthepotentialco-evolutionofHIVand HLA.Nature.2004;432:769–74.
7.RenéC,LozanoC,EliaouJ-F.ExpressionofclassicalHLAclass Imolecules:regulationandclinicalimpacts.HLA.
2016;87:338–49.
8.FarquharC,Rowland-JonesS,Mbori-NgachaD.Human leukocyteantigen(HLA)B*18andprotectionagainst mother-to-childHIVtype1transmission.AIDSResHum Retroviruses.2004.
9.PolycarpouA,NtaisC,KorberBT,etal.Associationbetween maternalandinfantclassIandIIHLAallelesandoftheir concordancewiththeriskofperinatalHIVtype1 transmission.AIDSResHumRetroviruses.2002;18:741–6. 10.MacDonaldKS,EmbreeJ,NjengaS,etal.Mother–childclassI
HLAconcordanceincreasesperinatalhuman
immunodeficiencyvirustype1transmission.JInfectDis. 1998;177:551–6.
11.MackelprangRD,CarringtonM,John-StewartG,etal. MaternalhumanleukocyteantigenA*2301isassociatedwith increasedmother-to-childHIV-1transmission.JInfectDis. 2010;202:1273–7.
12.Arnaiz-VillenaA,Martín-VillaJM,AmadorJTR,etal.Riskof verticalHIVtransmissioncombinesthe“B35-Cw4
disadvantage”andthe“patternofinheritance”theoriesof progression.CurrHIVRes.2009;7:314–9.
13.KaslowRA,CarringtonM,AppleR,etal.Influenceof combinationsofhumanmajorhistocompatibilitycomplex genesonthecourseofHIV-1infection.NatMed.
1996;2:405–11.
14.GaoX,BashirovaA,IversenAKN,etal.AIDSrestrictionHLA allotypestargetdistinctintervalsofHIV-1pathogenesis.Nat Med.2005;11:1290–2.
15.AltfeldM,AddoMM,RosenbergES,etal.Influenceof HLA-B57onclinicalpresentationandviralcontrolduring acuteHIV-1infection.AIDS.2003;17:2581–91.
16.MiguelesSA,SabbaghianMS,ShupertWL,etal.HLAB*5701is highlyassociatedwithrestrictionofvirusreplicationina subgroupofHIV-infectedlongtermnonprogressors.ProcNatl AcadSci.2000;97:2709–14.
17.SchneidewindA,TangY,BrockmanMA,etal.Maternal transmissionofhumanimmunodeficiencyvirusescape mutationssubvertsHLA-B57immunodominancebut facilitatesviralcontrolinthehaploidenticalinfant.JVirol. 2009;83:8616–27.
18.ThobakgaleCF,PrendergastA,CrawfordH,etal.Impactof HLAinmotherandchildondiseaseprogressionofpediatric humanimmunodeficiencyvirustype1infection.JVirol. 2009;83:10234–44.
19.KuhnL,AbramsEJ,PalumboP,etal.Maternalversuspaternal inheritanceofHLAclassIallelesamongHIV-infected children:consequencesforclinicaldiseaseprogression.AIDS. 2004;18:1281–9.
20.AdlandE,PaioniP,ThobakgaleC,etal.Discordantimpactof HLAonviralreplicativecapacityanddiseaseprogressionin pediatricandadultHIVinfection.PLoSPathog.2015;11: 1–26.
21.WinchesterR,PittJ,CharuratM,etal.Mother-to-child transmissionofHIV-1:strongassociationwithcertain maternalHLA-Ballelesindependentofviralloadimplicates innateimmunemechanisms.JAcquirImmuneDeficSyndr. 2004;36:659–70.
22.RaymondM,RoussetF.GENEPOP(version1.2):population geneticssoftwareforexact-testsandecumenicism.JHered. 1995;86:248–9.
23.PaximadisM,MinevichG,WinchesterR,etal.KIR-HLAand maternal–infantHIV-1transmissioninsub-SaharanAfrica. PLoSOne.2011;6.
