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TheJournalofInfectiousDiseases
EDITORIAL
MeasuringtheHaystack’s Needles
David 
DepartmentofMedicine,DivisionofInfectiousDiseases,UniversityofNorthCarolinaHIVCureCenter,ChapelHill,NorthCarolina,USA,DepartmentofMicrobiologyandImmunology,Universityof
NorthCarolinaatChapelHillSchoolofMedicine,ChapelHill,NorthCarolina,USA,andDepartmentofEpidemiology,UniversityofNorthCarolinaatChapelHillSchoolofPublicHealth,ChapelHill,
NorthCarolina,USA
Downloadedfrom-article/doi/
TotheEditor—Humanimmunodefi-andsimplybyDNApolymerasechaincell-associatedHIV-1ribonucleicacid
ciencyvirustype1(HIV)infectionhasreaction(PCR)assays,directmeasure-(RNA),andresidualplasmaviremia.
becomeamanageablechronicconditionmentofthetruerebound-competentBecauseithasbeenhypothesizedthat
asthesafetyandefficacyofantiretro-reservoirrequirestheuseofquantita-thepersistenceofHIVinfectiondespite
viraltherapy(ART)([QVOAs]ARTisdrivenbyHIV-relatedpersistent
Long-actingtherapiesareemergingthat[6,7]),adefinitiveandusefulmetricinflammationandT-cellactivationthat
mayremovethestigmaofdailydosing,thatistoocostlyanddemandingtobemaypersistdespiteART,changesinthese
butthemanyotherburdensofchronicwidelyapplied,particularlyinbroadparametersovertimewerealsoassessed
HIVinfectionstilldriveHIVcurere-
 al[8]havedescribedacleverofpeopleonARTwithlong-termsup-
CentralchallengestoresearchersdropletdigitalPCRassayofHIVDNApressionofviremia.
seekingtounderstandpersistentHIVdesignedtotakeadvantageofprobesGandhiet alobtainedsamplesfrom50
infectionanddevelopcurativeinter-thattarget2ampliconsfromrelativelyPWHwhohadenrolledinAIDSClinical
ventionsarethedemandinglabora-conservedregionsoftheHIVgenome,TrialsGroupStudyA5321andremained
toryassaysrequiredtoquantitatetheandtherebyidentifygenomeslikelytoinfollow-upwithplasmaHIV-1RNA
stablebutinducibleviralreservoirinlackmutationsordeletions:theIntactlevels<50copies/mLbycommercialas-
peoplewithHIVinfection(PWH)onProviralDNAAssay[IPDA].OneIPDAsaysstartingatweek48ofARTandatall
-
genomesthatarecompetenttopro-signalregionΨ,andtheother,-
duceinfectiousvirionsresidesprinci-env5’deletions,oftenresultsinthelosspants,IPDAfailedtoamplifyviralDNA
pallyinrestingcentralmemoryCD4+oftheΨamplicon,whereas3’deletionsin6(12%),presumablyduetoviralse-
Tcells,
ofT-celldifferentiationandprolifera-,
tion,proviralclonesmayexpandtotheamplicons(Figure 1,quadrant2) indi-butevenwithinCladeBcohortsassay
effectormemorypoolaswell[1–3].
However,thequantificationofCD4+replication- al[8]studiesindiversecohortsareexpectedto
Tcellscarryingintactprovirusesthatfound,inalimitedcohort,thatlevelsofclarifythefrequencyofassayfailure:one
candriveviralreboundisobscuredbyintactproviralDNAmeasuredwiththestudyof400patientsfindsafailurerate
alargepopulationCD4+cellscarryingIPDAcorrelatewithlevelsofreplication-%[9].
defectiveHIVdeoxyribonucleicacidcompetentHIV-1assessedbythevirusSamplesfromparticipantswereassayed
(DNA)genomes[4,5].Althoughtheoutgrowthassaybutare,onaverage,50-at3timepointsfollowingdurableART:
totalpopulationofthefewreplication-to100-fold ,, years
,40of
genomescanbemeasuredaccuratelyDiseases,Gandhiet al([9],pgX)ex-theremaining44participantswerefully
pandedtheassessmentoftheperfor-assessed,becausesamplesfrom4were
Received17August2020;editorialdecision17August2020;determinewhethertheintactproviralprotocol--
accepted17August2020;publishedonlineAugust21,2020.
DNAreservoirasmeasuredbyIPDAde-ulationwasreflectiveofthecurrentUS
TheJournalofInfectiousDiseases® 2020;XX:1–3
©TheAuthor(s),ifso,howepidemic,with50%blackandHispanic
-participants,ameanageof41 years,27%
Forpermissions,e-mail:journals.******@.+
DOI:-1persistence:HIV-1DNA,women,amediangainof429/µLCD4
MeasuringtheHaystack’sNeedles • jid 2020:XX (XXXXXX) • 1
Q1:HypermutatedQ2:IntactDisclosureofPotentialConflictsof
band/or3′deletion
-
siderrelevanttothecontentoftheman-
4000uscripthavebeendisclosed.
+–++–+References
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(Q2).FromFigure2[8].
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half- years;95%confidencein-sityinsomecohortsorpopulations;inPollack RA,et -
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withintherangeobservedbyCrookset alhavebeendevelopedtoallowtheuseprovirusesinthelatentreservoir
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et alstudy[9].begintofindsuccess,therelativeeaseoftentHIV-1reservoir:implications
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(Q1andQ4,Figure 1)didnotsubstan-relativelylownumberofperipheralblood2015;212:1361–5.
-lifeoftotalcells, JD,Kajdas J,Finzi D,et al.
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correlatedwithtotalHIV-1DNAandre-
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provirallevelsandinflammationorim- RT,Cyktor JC,*** RJ,
muneactivation,. reportspersonalfeesfromet al.;
reportedinastudythatusedQVOAandMerckandViiVHealthcareandholdsdecayofintactHIV-1proviralDNA
acohortofmenandwomen[11].havesubmittedtheICMJEFormfor2020;XX:YY–YY.
2 • jid 2020:XX (XXXXXX) • Margolis
 FR,White JA, AM,Simonetti FR,estimatedbytheintactproviral
Tumiotto C,et  MR,et 
DNAassayanalysisoflargeco-persistentviralgenomesinART-oftotalandintegratedDNAinthe
hortsofpeoplewithHIVprovidestreatedSIV,SHIV,andHIV-2in-bloodduringsuppressiveantire-
;troviraltherapy[publishedonline
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;defectiveproviralDNAinHIV-1-
latentHIVreservoirduringsuppressive130:3543–-
 E,Azzoni L,Ross BN,;
doi: :e132997.
MeasuringtheHaystack’sNeedles • jid 2020:XX (XXXXXX) • 3