Clinical, epidemiological and molecular features of the HIV-1 subtype C and recombinant forms that are circulating in the city of São Paulo, Brazil
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Clinical, epidemiological and molecular features of the HIV-1 subtype C and recombinant forms that are circulating in the city of São Paulo, Brazil

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10 pages
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Description

The city of Sao Paulo has the highest AIDS case rate, with nearly 60% in Brazil. Despite, several studies involving molecular epidemiology, lack of data regarding a large cohort study has not been published from this city. Objectives This study aimed to describe the HIV-1 subtypes, recombinant forms and drug resistance mutations, according to subtype, with emphasis on subtype C and BC recombinants in the city of São Paulo, Brazil. Study design RNA was extracted from the plasma samples of 302 HIV-1-seropositive subjects, of which 211 were drug-naive and 82 were exposed to ART. HIV-1 partial pol region sequences were used in phylogenetic analyses for subtyping and identification of drug resistance mutations. The envelope gene of subtype C and BC samples was also sequenced. Results From partial pol gene analyses, 239 samples (79.1%) were assigned as subtype B, 23 (7.6%) were F1, 16 (5.3%) were subtype C and 24 (8%) were mosaics (3 CRF28/CRF29-like). The subtype C and BC recombinants were mainly identified in drug-naïve patients (72.7%) and the heterosexual risk exposure category (86.3%), whereas for subtype B, these values were 69.9% and 57.3%, respectively (p = 0.97 and p = 0.015, respectively). An increasing trend of subtype C and BC recombinants was observed (p < 0.01). Conclusion The HIV-1 subtype C and CRFs seem to have emerged over the last few years in the city of São Paulo, principally among the heterosexual population. These findings may have an impact on preventive measures and vaccine development in Brazil.

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Publié par
Publié le 01 janvier 2012
Nombre de lectures 12
Langue English

Extrait

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RESEARCH

OpenAccess

Clinical,epidemiologicalandmolecularfeatures
oftheHIV-1subtypeCandrecombinantforms
thatarecirculatinginthecityofSãoPaulo,Brazil
RosanaAlcalde
1*

,MonickLGuimarães
3

,AlbertoJSDuarte
1
andJorgeCasseb
1,2*

Abstract
Background:
ThecityofSaoPaulohasthehighestAIDScaserate,withnearly60%inBrazil.Despite,several
studiesinvolvingmolecularepidemiology,lackofdataregardingalargecohortstudyhasnotbeenpublishedfrom
thiscity.
Objectives:
ThisstudyaimedtodescribetheHIV-1subtypes,recombinantformsanddrugresistancemutations,
accordingtosubtype,withemphasisonsubtypeCandBCrecombinantsinthecityofSãoPaulo,Brazil.
Studydesign:
RNAwasextractedfromtheplasmasamplesof302HIV-1-seropositivesubjects,ofwhich211were
drug-naiveand82wereexposedtoART.HIV-1partial
pol
regionsequenceswereusedinphylogeneticanalysesfor
subtypingandidentificationofdrugresistancemutations.TheenvelopegeneofsubtypeCandBCsampleswas
alsosequenced.
Results:
Frompartial
pol
geneanalyses,239samples(79.1%)wereassignedassubtypeB,23(7.6%)wereF1,
16(5.3%)weresubtypeCand24(8%)weremosaics(3CRF28/CRF29-like).ThesubtypeCandBCrecombinants
weremainlyidentifiedindrug-naïvepatients(72.7%)andtheheterosexualriskexposurecategory(86.3%),whereas
forsubtypeB,thesevalueswere69.9%and57.3%,respectively(p=0.97andp=0.015,respectively).Anincreasing
trendofsubtypeCandBCrecombinantswasobserved(p<0.01).
Conclusion:
TheHIV-1subtypeCandCRFsseemtohaveemergedoverthelastfewyearsinthecityofSãoPaulo,
principallyamongtheheterosexualpopulation.Thesefindingsmayhaveanimpactonpreventivemeasuresand
vaccinedevelopmentinBrazil.
Keywords:
HIV-1,Subtypes,Recombinants,Resistance,SãoPaulo,Brazil

Background
genotypingsystems[1-3].Thus,HIV-1subtypesalso
ThehugegeneticvariabilityofHIV-1resultsinacom-contributetothecapacityofHIV-1toevadethehost
plexanddynamicmolecularclassificationoftypes(HIV-immuneresponse,[4]whichcanaffecttheresponseto
1and2),groups(M,N,O,P),andthepandemicgroupMantiretroviraltreatmentand,consequently,totheemer-
couldbedividedintosubtypes(A-D,F-H,J,K)andrecom-genceofdrugresistance[5].Somestudieshavesug-
binantforms,suchascirculatingrecombinantformsgestedthatcoreceptorswitchingfromCCR5toCXCR4
(CRF)anduniquerecombinantforms(URF).SuchHIV-islesscommoninHIV-1subtypeC,[6]showingalower
1variationhasanimportantimpactondiagnosis,viralrateofaccumulationofmutationsthatconferresistance
loadmeasurementandtheperformanceofHIV-1thansubtypeB[5].Concerningthereplicationfitnessof
subtypeC,thestudieswerecontroversial,[7-9]andin
*Correspondence:rosana117@yahoo.com;jcasseb@usp.br
relationtotransmissioninutero,thissubtypepresented

Equalcontributors
1
LaboratoryofDermatologyandImmunodeficiencies,Departmentof
highefficiencycomparedtosubtypesAorD[8,10,11].
Dermatology,MedicalSchoolofSãoPauloUniversity,LIM56/FMUSP.Av.Dr.
Thesepropertiessuggestanoveralltransmissionadvan-
EneasdeCarvalhoAguiar,470,IMTII,3°andar,05403-000SãoPaulo,SP,
tage,inpart,possiblyrelatedtoefficientreplicationin
Brazil
Fulllistofauthorinformationisavailableattheendofthearticle
©2012Alcaldeetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.

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dendriticcells,thetargetsoftheonsetofHIV-1infec-
tion[11].
AlthoughHIV-1subtypeBisthemoststudied,HIV-1
Cpredominatesgloballyandisresponsibleforapproxi-
mately50%ofinfections[12].Thissubtypeisnotwide-
spread,butitisthemostprevalentinsub-Saharan
Africaandinthepopulouscountries,suchasIndiaand
China,whereHIVinfectionratesarehighestamonghet-
erosexuals[12,13].Uptonow,fivecirculatingrecombin-
antforms(CRFs)involvingthissubtypehavebeen
detected,threeofthempresentingrecombinationsbe-
tweensubtypesBandC,CRF07,CRF08,describedin
China,[14,15]andCRF31_BC,describedinBrazil[16].
Theothertwopresentrecombinationsbetweensubtypes
CandD,CRF10_CDandCRF41_CD[17,18].Overall,
morethan18%ofnewinfectionshavebeenattributedto
HIV-1recombinants[19].
TheBrazilianAIDSepidemicismainlydrivenby
subtypesB,F1,andBF1recombinants;however,inthe
Southernregion,subtypeCandBCrecombinantscan
representupto50%ofcases,dependingofthegeo-
graphicalstudiedregion[20-27].Despitethedocumen-
tedearlycirculationofHIV-1subtypeCoutsideofthe
southernregionin1992,onecasefromthecityofSão
Paulo[28]andanotherin1986inSantos,[29]only
recentlyhasacontinuousincreaseincasesbeen
observed[30-32].
ThecurrentstudywasconductedtodetermineHIV-1
geneticdiversityandPI/RTIresistanceassociatedmuta-
tionsamongHIV-1infecteddrugnaïveandHAART
patientsinacohortinthecityofSãoPaulo.Moreover,
patientsclassifiedasHIV-1subtypeCandBCrecombi-
nantswereanalyzedinmoredetails.
Objectives
ThepresentstudyaimedtodescribeHIV-1subtypes,
CRFsanddrugresistancemutationsindrug-naïveand
failingHAARTindividualslivinginthecityofSão
Paulo,inparticularattentiontothoseclassifiedassub-
typeCandBC.
Studydesign
Studypopulation
ThestudypopulationwascomposedbyHIV-1-infected
patientswhohavebeenfollowed-upattheAmbulatory
ServiceoftheDepartmentofSecondaryImmunodeficiency
ClinicoftheClinicalHospital,UniversityofSãoPaulo
MedicalSchool(HC/FMUSP),SãoPaulo,SP,Brazil,oneof
thelargestteachingandresearchhospitalsinBrazil.
AccordingtotheBrazilianMinistryofHealth,HIV
genotypingtestshouldberoutinelyperformedin
patientsunderantiretroviraltherapywhopresenta
plasmaviralloadover2000copies/mL[33].Following
thisdirective,atotalof82patientsweregenotypedat

Page2of10

HC/FMUSPfromMarch2002toJune2010.Duringthe
sameperiod,211drug-naiveindividualsandnineindivi-
dualswhohadunknownstatusinrelationtoantiretro-
viraltherapy(ART)werealsogenotyped.Demographic
andclinicaldatawereobtainedfromclinicalchartsor
directinterviewandthepatientsindividuallyallowus
forpublication,asshownatTable1.Thisstudyprotocol
wasapprovedbytheResearchEthicsCommitteeofHC/
FMUSP,underprotocolnumber774/99,andwritten
informedconsentwasobtainedfromallpatients.During
+thefollow-up,CD4TcellsandHIV-1viralloadwere
determinedusingtheBrazilianMinistryofHealth
guidelines.
RNAisolation,RT-PCRandDNAsequencing
HIV-1viralRNAwasisolatedfromplasmasamples
usingtheQIAamp
W
ViralRNAMiniKit(Qiagen,Hilden,
Germany)extractionmethod,inaccordancewiththe
manufacturer

sprotocol.ComplementaryDNAwasper-
formedbyRT-PCRprotocolwithrandomprimersand
usingthePR/RTPCRstrategypreviouslydescribedby
Gonzalesetal.[34,35].ThePCRproductswerepuri-
fiedusingQIAquick
W
(Qiagen,Hilden,Germany),in
accordancewiththemanufacturer

sprotocol.ThePCR
purifiedproductsweresequencedutilizingABIPrismBig
DyeTerminatorReadyReactionKitversion3.0(Applied
Biosystems
W
,FosterCity,CA),inaccordancewiththeirre-
spectiveprotocols.Thereactionswereanalyzedusingthe
ABIPrism3100GeneticAnalyzer(AppliedBiosystems
W
,
FosterCity,CA).
Sequenceanalysis
ThechromatogramsofallsequencedDNAwerevisu-
allyusingtheSequencherprogramversion4.0.5(Gene
Codes)andmanuallyedited.PR/RTsequencingwas
conductedtodetectdrugresistancemutationsand
HIV-1subtypes.Majorantiretroviraldrugresistance
mutationswereclassifiedaccordingtoStanfordUni-
versityonlineHIVDrugResistanceDatabase,[36].
TheInternationalAIDSSociety-USAPanelandUp-
dateoftheDrugResistanceMutationsinHIV-1,
Spring2008[37-39].
NucleotidesequenceswerealignedusingtheClustalX
program[40]andlaterhandeditedforminoradjust-
mentsandgap-stripped.Analignmentof860bpthat
partiallycoveredthePR/RTregion(nucleotides2343-
3203)wasusedforphylogeneticinferencesunder
Neighbor-Joining(NJ)algorithminMega4.0.2program
[41].Inordertoconfirmtheclassificationofthenon-B
sequences,Bayesiananalysiswasperformed.ThejMo-
deltest0.1.1program[42]wasusedtoselectthebest-fit
modelofnucleotidesubstitutionundertheAkaikeinfor-
mationcriteria,resultinginthechoiceoftheGTR+I+
Gmodel,[43]asimplementedinMrBayesv3.1.2[44].

Table1Epidemiological,virological,immunologicalcharacteristicsandresistanceassociatedmutationsofPR/RTregionfrompatientsclassifiedasHIV-1
I.D.LIM56DateAgeGenderVLCD4TransmissionMutationsMutationsotherMutationsMutationsMutationsother(RT)
collection(years)modeProtease(Protease)(NRTI)(NNRTI)
orinmA-subtypeC
0122/09/200348
0225/09/200363
0318/04/200531
0423/05/200522

5006708009

0111

21

31

14

11/08/200537
13/09/200537
10/04/200639
11/05/200644
03/08/200623

09/04/200725
4/5/200930

4/5/200929

8/4/201031

1

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