enterwww.7788k.com

GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30OpenAccessREVIEWBioMedCentral2010GrasandKaul;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
ReviewMolecularmechanismsofneuroinvasionbymonocytes-macrophagesinHIV-1infectionGabrielGras*1andMarcusKaul2AbstractHIVassociatedneurocognitivedisordersandtheirhistopathologicalcorrelateslargelydependonthecontinuousseedingofthecentralnervoussystemwithimmuneactivatedleukocytes,mainlymonocytes/macrophagesfromtheperiphery.
Theblood-brain-barrierplaysacriticalroleinthisneverstoppingneuroinvasion,althoughitappearsunaltereduntilthelatestageofHIVencephalitis.
HIVfluxthatmovestowardthebrainthusreliesonhijackingandexacerbatingthephysiologicalmechanismsthatgovernbloodbrainbarriercrossingratherthanbarrierdisruption.
ThisreviewwillsummarizetherecentdatadescribingneuroinvasionbyHIVwithafocusonthemolecularmechanismsinvolved.
IntroductionHIV-1infectionisoftenassociatedwithneurocognitiveimpairmentandthevariousdegreesofseverityhaverecentlybeencategorizedundertheoverarchingtermHIVassociatedneurocognitivedisorders(HAND)[1].
HANDdefinesthreecategoriesofclinicaldisordersaccordingtostandardizedmeasuresofdysfunction:i)asymptomaticneurocognitiveimpairment(ANI),ii)mildneurocognitivedisorder(MND)andiii)HIV-associateddementia(HAD)[2].
HADconstitutesthemostsevereformofHAND[1]whichpresenteditselfprominentlyatthebeginningoftheAIDSepidemicbutprimarilyinpatientswithlowCD4+cellcountsandadvancedHIVdisease[3].
Intro-ductionofcombinationanti-retroviraltherapy(cART)/highlyactiveantiretroviraltherapy(HAART)inthemid1990improvedtreatmentofHIVinfectionandoftenpre-ventedoratleastdelayedtheprogressiontoAIDSandHAD.
Inrecentyears,however,andsinceHIVpatientslivelonger,theincidenceofdementiaasanAIDS-defin-ingillnesshasincreased,andHADnowdefinesasignifi-cantindependentriskfactorfordeathduetoAIDS[4,5].
WhileintheHAARTeraMNDappearstobemoreprev-alentthanfrankdementia,itappearsimportanttotaketheselonglastingdisordersintoaccountinpatients'fol-lowupastheymayprofoundlyaffectqualityoflife,com-plicateautonomy,modifytreatmentcomplianceandinduceahighlevelofvulnerability.
Moreover,clinicalobservationsovermorethan10yearsalsosuggestthatHAARTcannotcompletelyprotectfromHAD[1,4-7].
Inaddition,itispossiblethatlife-longtreatmentwithHAARTitselfgeneratesatoxicologicalproblemwhichmayaffectneurocognitiveperformanceonitsown[5,8].
TheneuropathologicalcorrelatesofHIV-1infectionaregenerallyreferredtoasHIVencephalitis(HIVE)andcomprisemicroglialnodules,activatedresidentmicro-glia,multinucleatedgiantcells,infiltrationpredomi-nantlybymonocytoidcells,includingblood-derivedmacrophages,widespreadreactiveastrocytosis,myelinpallor,anddecreasedsynapticanddendriticdensityincombinationwithdistinctneuronalloss[9-11].
HIV-1associatedneuronaldamageandlosshavebeenreportedfornumerousregionsofthecentralnervoussystem(CNS),includingfrontalcortex[12,13],substantianigra[14],cerebellum[15],andputamen[16].
TheneuropathologyofHIVinfectionandAIDShaschangedundertheinfluenceofHAART[6,7,17].
Neu-roinflammationwascommonlyobservedinHIVpatientsatthebeginningoftheAIDSepidemicandbeforetheintroductionofHAART,andusuallyincreasedthrough-outtheprogressionofinfectedindividualsfromthelatent,asymptomaticstageofthediseasetoAIDSandHAD[18].
Surprisingly,neuroinflammationseemstopersistorevenflourishsincetheadventofHAART[17,19].
AutopsystudiesinrecentyearsfoundmicroglialactivationcomparabletothatinfullydevelopedAIDS*Correspondence:gabriel.
gras@cea.
fr1InstituteofEmergingDiseasesandInnovativeTherapies,DivisionofImmuno-Virology,CEA,18RouteduPanorama,F92265Fontenay-auxRoses,FranceFulllistofauthorinformationisavailableattheendofthearticleGrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page2of11casesfromthepre-HAARTera,althoughtheprimarysitesofneuroinflammationareseeminglychanged.
Dur-ingpre-HAARTtimesastronginvolvementofthebasalgangliawasobservedwhereaspost-HAARTspecimendisplayedprominentsignsofinflammationinthehip-pocampusandadjacentpartsoftheentorhinalandtem-poralcortex[17].
Interestingly,HAARTappearedtolimitorevenpreventlymphocyteinfiltrationintotheCNSwiththeexceptionoftheoccasionallyoccurringimmunereconstitutioninflammatorysyndrome(IRIS),thatischaracterizedbymassivelymphocytosis,extensivedemy-elinationandwhitematterdamage[6,17].
HIV-1entersthebrainearlyinthecourseofinfection,presumablyviainfectedmacrophagesandlymphocytes,andthenpersistsprimarilyinperivascularmacrophagesandmicroglia[11,20,21].
Thepathophysiologicalrele-vanceofCNSinvadinglymphocytesinHANDremainstobeestablished[22],butCD8+TcellshavebeensuggestedtocontrolintrathecalHIVreplication[23].
Incontrasttolymphocytes,anincreasednumberofmicrogliaandmac-rophagescorrelateswellwiththeseverityofpre-mortemHAND[11,18,24].
InfectionoftheCNSbyHIV-1canbedetectedandmonitoredbymeasurementofviralRNAincerebrospinalfluid(CSF).
Severalgroupshavereportedapositivecor-relationbetweenCSFviralloadandtheobserveddegreeofcognitivedysfunctioninpatientswithHAND[25-27].
Moreover,CSFviralloadappearstocorrelatewithviralloadinbrainmeasuredbyquantitativePCR[27,28],andthehighestconcentrationsofvirusareobservedinthosesubcorticalstructuresmostfrequentlyaffectedinpatientswithsevereHAND/HAD[28].
However,inadditiontoinitialneuroinvasionandinfec-tionofperivascularmacrophagesandmicroglia,factorsassociatedwithprogressiveHIVinfectionintheperiph-ery,thusoutsidethebrain,mayberequiredtoeventuallytriggerthedevelopmentofHANDanddementia[29].
Onesuchfactorcouldbeanelevatednumberofcirculat-ingmonocytesexpressingtwomarkersofactivatedmonocytes,CD16andCD69.
Anotherimportantplayermaybethebloodbrainbarrier(BBB)whichseparatestheCNSfromtheperipheryandsupposedlycontrolsthetrafficoflow-molecular-weightnutrients,peptides,pro-teinsandcellsinandoutofthebrain(seeforBBBreview[30]).
ThustheconditionoftheBBBmaypotentiallydeterminecontinuingorrepeatedneuroinvasionduringthecourseofHIVdisease.
However,themolecularmech-anismsunderlyingHIVneuroinvasionareonlyslowlyemerging.
ThisreviewwilldiscussrecentprogressinstudiesofcellularandmolecularfactorsaffectingHIVneuroinvasionandconsequentneurocognitivesequelae.
PeripheralFactorsInfluencingHIV-1NeuroinvasionWhileinterferons(IFNs)areimportantforananti-viralimmuneresponse,thelastingproductionofIFN-αand-γinHIV-1infectionhasbeenlinkedtoanerroneousandexhaustiveimmuneactivationleadingeventuallytoimmunesuppressionandprogressiontoAIDS[31-33].
Inaddition,thesustainedpresenceofIFN-αintheHIV-infectedCNScorrelateswithneurocognitiveimpairment[34,35].
Therefore,IFNsappeartohaveindeedamajorimpactontheoverallcourseofHIVdiseaseandconse-quentlyalsoonthedevelopmentofHAND.
However,itisnotwellunderstoodwhetherornotIFNsdirectlyinflu-enceneuroinvasionofHIV-1.
OnepossibleeffectmaybetheIFN-inducedexpressioninthehumanBBBofAPOBEC3G,whichhasbeensuggestedtoaccountforthelimitedabilityofhumanbrainmicrovascularendothelialcells(HBMEC)tosupportHIV-1replicationandthusdisseminationintothecentralnervoussystem[36].
Peripherallycirculating,activatedCD16+CD69+monocytesarepronetoadheretonormalendotheliumofthebrainmicrovasculature;theytransmigrateandmightsubsequentlytriggeranumberofdeleteriousprocesses[29].
Moreover,CD16+monocytesbecomeanexpandingimmunecellpopulationduringHIVinfection[37],par-ticularlywithprogressiontoAIDS[38].
TheseCD16+monocytesarealsomoresusceptibletoHIVinfectionthantheCD16-subsetandarethemajorHIVreservoiramongmonocytesinvivo[39,40].
Infact,CD16+mono-cyteslikelyserveasavectorforHIVtraffickingfromtheperipheryintothebrain[29,41].
Indeed,althoughmostmonocytesdonotactivelyreplicatethevirus,themac-rophagesthatdifferentiatefromtheseinfectedmono-cyteslikelyproducelargeamountsofvirusaftertheyquitthecirculation,consideringthatdifferentiatedmac-rophagesaremorepronetoreplicatingHIVthanmono-cytes[42-48].
Furthermore,CD16+monocytes/macrophagescansupportHIVreplicationinT-lympho-cytes[49]andmaybesequesteredbytissuesexpressingtheδ-chemokineFractalkine(Fkn/CX3CL1),whichincludethebrainbesideslymphnodesandintestine[50-52].
Theseactivatedmonocytesthatrepresentalatentprovirusreservoirintheblood[40]thusmaycontinu-ouslyre-seedthebrainwithinfectedmacrophagesandmicroglia.
Inaddition,macrophagesandmicrogliadoreplicateHIVinthebrain[11,20,21,53]andarenotsus-ceptibletothevirus'cytopathiceffects[54,55]thusper-mittingthemtoproducevirionsthroughouttheirlonglifespan[56-58].
InbothHIVEandsimianimmunodeficiencyvirusencephalitis(SIVE),CD163+/CD16+macrophagesaredetectedintheparenchymaofthebrainandseemtorep-resenttheprimaryproductivelyinfectedcellpopulation[53].
TheelevatednumberofCD163+/CD16+monocytes/macrophagesmayreflectanalterationofperipheralmononuclearcellhomeostasisandisassociatedwithincreasedviralburdenandreductionofCD4+Tcells.
InSIVinfectionincreasedviralburdenisassociatedwithdevelopmentofencephalitis,andsuggeststhattheGrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page3of11CD163+/CD16+monocyte/macrophagesubsetmaybeimportantinHIV/SIV-associatedCNSdisease[53].
ThecriticalroleofmacrophagesintheHIV-infectedbrainisfurthersupportedbytheviralcoreceptorusage.
CCR5isthemaincoreceptorforHIVinfectionofmacrophagesandmicroglia[59-61],andmostvirusisolatesfoundinthebrainortheCSFuseCCR5[60,62-68].
Ofnote,theveryrarebrain-derivedR5X4isolatesexhibittissuespe-cificchangesintheV3regionofgp120thatincreasetheefficiencyofCCR5usageandenhancetheirtropismformacrophagesandmicroglia[69].
Moreover,macrophagetropismratherthanR5tropismappearstopredictneu-rotropism[67],furtheremphasizingtheroleofthesecellsinNeuroAIDS.
Onerecentstudyusedfluorescein-positivemonocytesinacutesimianimmunodeficiencyvirusinfectiontotrackneuroinvasion[70].
Inthisstudyemployingrhesusmacaques,fluoresceindye-labeledautologousleukocyteswereintroducedintheperipheryfromwherethecellssubsequentlyenteredintothechoroidplexusstromataandperivascularlocationsinthecerebraduringacuteSIVinfection.
TheinfiltratedcellsdisplayedbothCD16andCD68,bothmarkersformacrophagesandmicroglia.
Theneuroinvasionofmonocytesoccurredsimultane-ouslywithdetectableamountsofvirusinCNStissueandCSF.
Furthermore,neuroinvasionwasaccompaniedbytheappearanceoftheproinflammatorychemokinesCXCL9/MIGandCCL2/MCP-1inthebrain.
Interest-ingly,beforeneuroinvasionbecameobvious,plasmaviralloadpeaked;countsofperipheralbloodmonocytesrap-idlyincreased;andcirculatingmonocytesdisplayedanelevatedcapacitytogenerateCCL2/MCP-1.
Acuteinfil-trationofmonocytesintothebrainisthuscentralinearlyneuroinvasionintheSIVanimalmodelofAIDS.
BesidesaprominentroleofmigratorymonocytesforSIV/HIVneuroinvasion,thisstudysuggestedthatadisturbanceoccursatthebarriersbetweenbloodandbrainparen-chymaaswellasbloodandCSF[70].
AsanalternativetoHIVentryviainfectedmac-rophages,ithasbeensuggestedthattheinflammatorycytokineTNF-αpromotesapara-cellularrouteforthevirusacrosstheBBB[71].
However,inastudyinthefelineimmunodeficiencyvirusmodel,cell-freeFIVcrossedtheBBBonlyinverylowquantities[72].
More-over,thepresenceofTNF-αdidnotchangeviraltransferorcompromiseBBBintegrity.
Incontrast,FIVreadilycrossedtheBBBwhencell-associated,yetwithoutanysignificantimpairmentoftheBBB.
InresponsetoTNF-α,themigratoryactivityofuninfectedandinfectedlympho-cytesincreasedinassociationwithanup-regulationofvascularendothelialadhesionmolecule(VCAM)-1andsomedetectabledisturbanceoftheBBB.
Interestingly,onceinfectedcellsandTNF-αwereintroducedontheabluminalsideoftheBBBinthebrainparenchyma,anadditionalenhancedcellinfiltrationandmorepro-nounceddisruptionoftheBBBensued.
Moreover,thesamestudyconcludedthatCNSinvasionoflymphocyte-tropiclentivirusesisessentiallyverysimilartothatofmacrophage-tropicstrains[72].
HIV-1infectioncompromisesthestructuralintegrityoftheintestinaltractandcancauseleakageofbacteriaintothebloodstream.
Suchmicrobialtranslocationresultsinelevatedplasmalevelsofbacteriallipopolysaccharide(LPS),andinHIV-infected/AIDSpatients,isassociatedwithincreasedmonocyteactivationanddementia[73-75].
AnotherstudysuggeststhatHIVinfectionincreasesthevulnerabilityoftheBBBinresponsetoLPSandfacili-tatesthetransmigrationofperipheralmonocytes/mac-rophages[76].
ThesefindingssupportanimportantroleforToll-likereceptors(TLRs)besidesmonocytesandmacrophagesinHAD[75,76].
Onthepartofthehost,aviciouscycleofimmunedys-regulationandBBBdysfunctionmightberequiredtoachievesufficiententryofinfectedoractivatedimmunecellsintothebraintocauseneuronalinjury[77,78].
Onthesideofthevirus,variationsoftheenvelopeproteingp120mightalsoinfluencethetimingandextentofeventsallowingviralentryintotheCNSandleadingtoneuronalinjury[79].
Blood-Brain-Barrier(BBB)TheBBBiswidelybelievedtoplayanimportantroleinHIVinfectionoftheCNS[29,80].
Forexample,anacuterelapsingbrainedemawithdiffuseBBBalterationsandaxonaldamagewasobservedearlyduringtheAIDSepi-demic[81];andtheextravasationofplasmaproteinthroughanalteredBBBhaslongbeendescribedinAIDSandHIVEcases[82].
Invivo,increasedpermeabilityoftheBBBfollowingHIV/SIVneuroinvasionisassociatedwiththedisorganizationoftightjunctions[83].
Inpartic-ularzonulaoccludens(ZO-1)expressionismodifiedinbrainsofpatientswithHIVencephalitis[71,84],andlossofoccludinandclaudin-5correlateswithareasofmono-cytesinfiltration[85].
SuchmodificationsofmoleculesinvolvedinBBBstructurearealsofoundinthebrainofSIV-infectedmacaqueswithSIVE[86,87].
Nevertheless,theseprofoundmodificationsoftheBBBstructureappeartobelateeventsassociatedwithencephalitiswhereasneuroinvasionisanearlyandcontinuingpro-cess.
RegardingtheunderlyingmolecularmechanismsinvolvedinBBBcrossingbyHIV,itappearsappropriatetoconsiderinparticularthefollowingprocesses:HIV-dependentcytotoxicitytowardscellularBBBcompo-nents,chemotaxis,regulationofadhesionmoleculesandtightjunctionproteins,andlastnotleastthepotentialinfluenceofdrugsofabuse.
GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page4of11CytotoxicityTowardsCellularBBBComponentsTheHIVenvelopeproteingp120apparentlycantriggercytotoxicityinhumanbrainmicrovascularendothelialcells(HBMEC)[88].
TheprocessrequiredthepresenceofIFN-γandactivationofthep38mitogen-activatedpro-teinkinase(MAPK).
Interestingly,gp120-inducedcyto-toxicityoccurredonlyinHBMECfromchildrenbutnotfromadults.
ThetreatmentwithIFN-γresultedinanup-regulationofthechemokinereceptorsCCR3andCCR5inHBMECswhichinturnmayhaveenhancedthetoxicinteractionwiththeviralenvelopeprotein[88].
Interestingly,alterationsintheBBBoccurevenintheabsenceofintactvirusintransgenicmiceexpressingtheHIVenvelopeproteingp120inaformthatcirculatesinplasma[89].
ThisfindingsuggeststhatcirculatingvirusorenvelopeproteinsmayprovokeBBBdysfunctionatleastduringtheviremicphaseofprimaryinfection.
ChemotaxisNeurons,astrocytesandmicrogliaallproducechemok-ines-cellmigration/chemotaxisinducingcytokines-suchasmonocytechemoattractantproteinCCL2/MCP-1andCX3CL1/Fkn,whichappeartoattractperipheralbloodmononuclearcells(PBMC)acrosstheBBBintothebrainparenchyma[22,90].
Infact,anincreasedriskofHADhasrecentlybeenconnectedtoamutantMCP-1allelethatcausesincreasedinfiltrationofmononuclearphagocytesintotis-sues[91].
InHIV/SIVinfection,macrophages/microgliaandastrocytesexpressincreasedquantitiesofMCP-1/CCL2[92-94],achemokinethatefficientlyattractsmonocytesacrosstheBBB.
Numerouscelltypes,includ-ingmacrophages/microglia,astrocytesandendothelialcells,produceMCP-1inresponsetoinflammatorystimu-lation[95].
Ofnote,HIVinfectionofmacrophagesincreasedtheirexpressionoftheCCL2receptor,CCR2,andCCL2mediatedtransmigrationofHIV-infectedPBMCreducedtightjunctionproteinsoccludin,claudin-1andZO-1expressioninaBBBmodelinvitro[94].
Stud-iesbynumerousgroupssuggestedCCL2intheCNSasakeymoleculeforHIVencephalitis[96-100]duringwhichitaccumulatesintheCSFandbrainparenchyma[97,101].
MacaqueswithSIVEbehavesimilarly[100,102,103].
OfimportanceinHIVinfection[96]aswellasintheSIVmodel[100]isthattheCCL2concentrationrisesintheCSFbeforeneurologicalsignsofthediseaseoccur,con-ferringtotheconcentrationofCCL2apotentiallyprog-nosticvalue.
InamousemodelofHIVEbasedonanimalswithseverecombinedimmunodeficiency(HIVE-SCIDmodel),HIV-infectedmicrogliaandastrocytesseemedtoregulatemonocytemigrationacrosstheBBBviathereleaseofβ-chemokines[104].
Ontheotherhand,stromalcell-derivedfactor(SDF)-1/CXCL12,anα-chemokine,hasalsobeenfoundtoinfluencemigrationofmonocytesbyregulatingattachmentofthecellstoHBMECviatheβ2integrinlymphocytefunction-associ-atedantigen(LFA)-1inaLynkinasedependentfashion[105].
CXCL12isup-regulatedinneuroinflammatorydiseasessuchasHAND/HADormultiplesclerosis,andthesamestudyfoundthattheα-chemokineconcomi-tantlyreducedmonocyteadherencetointercellularadhe-sionmolecule(ICAM)-1,whichbindsβ2integrins.
Interestingly,CXCL12alsocounteractedtheeffectofTNF-α,IL-1βandHIVgp120regardinganincreaseofmonocyteattachmenttoHBMECduetoanup-regula-tionofICAM-1[105].
InlinewiththeseobservationsandimportantforthebetterunderstandingofHIV-CNSdis-ease,wefoundthatnervegrowthfactor(NGF)promotestheattractionofmonocytesbyCXCL12withapreferen-tialeffectontheCD16+subset[106],whileatthesametimedecreasingHIV-1replicationintheattractedandinfectedcells[107],suggestingaspecificattractionofuninfectedmonocytes.
UsinganinvitromodeloftheBBBcomprisedofendothelialcellsandastrocytes,anotherstudyfoundthatbothCXCL12andCCL2promotedtransmigrationofuninfectedmonocytesandlymphocytes[108].
ThisinvestigationalsorevealedthatHIV-1transactivatoroftranscription(Tat)inducedadhesionmoleculesandchemokinesinastrocytesandmicrogliawhichmayfur-therincreasethetraffickingofPBMCintothebrain.
Atthecellularlevelofmonocytesandmacrophages,thepro-migratoryeffectofCCL2appearstoinvolveK+channels[109].
ArecentmicroarraystudyofHBMECco-culturedwithHIV-infectedmacrophagesfoundtheinductionofnumerouspro-inflammatoryandIFN-induciblegenesincomparisontoendothelialcellsexposedtouninfectedimmunecells[110].
Inaseparateinvestigationbythesamegroup,HIVgp120wasobservedtotriggerinHBMECtheactivationofsignaltransducerandactivatoroftranscription(STAT)-1andthereleaseofinterleukin(IL)-6andIL-8[111].
Theeukaryoticinterleukinsandtheviralgp120promoted,inaninvitroBBBmodel,theattachmentandtransmigrationofmonocytes;andthoseprocesseswerepreventedbyinhibitorsofMAPKs,phos-phatidyl-inositol3kinase(PI3K)orSTAT-1[111].
Fur-thermore,thepro-inflammatoryandIFN-induciblegeneproductsreleasedbyHBMECuponexposuretoHIV-1havebeenfoundtodown-regulatetheexpressionoftightjunctionproteinsclaudin-5,ZO-1,andZO-2[112].
Inter-estingly,anincreaseofactiveSTAT1andareductionofclaudin-5werealsofoundinmicrovesselsofbrainspeci-mensfromHADpatients[112].
Ofnote,theHIV-1enve-lopeproteingp120seemstobeabletotriggermanyoftheeffectsleadingtoacompromisedBBBandenhancedmonocytetransmigration[113].
GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page5of11InlinewiththealteredgeneexpressionofHBMECexposedtoHIV-1infectedmacrophages,aproteomicstudyfoundthatover200proteinswereup-regulatedunderthesameconditions[114].
Theaffectedcellularcomponentsincludedmetabolicpathways,ionchannels,cytoskeletal,heat-shock,calcium-bindingandtransport-relatedproteins.
TranslocationofbacterialLPSfromtheintestineinHIV-1infectionmaynotonlypromotethecapabilityofperipheralmonocytestotransmigrateintothebrain,butmayalsoencounteraBBBweakenedbytheeffectsofasystemiclentiviralinfection.
Inatransgenicmousemodel,JR-CSF/EYFPmice,expressingbothalongtermi-nalrepeat-regulatedfull-lengthinfectiousHIV-1provirus(JR-CSF)andaROSA-26-regulatedenhancedyellowflu-orescentprotein(EYFP)astransgenes,peripheralmono-cyteshadanincreasedcapabilitytoenterthebrainthroughanintactorpartiallycompromisedBBB[76].
PartialimpairmentoftheBBBwasinducedbysystemicLPS.
Importantly,theBBBofJR-CSF/EYFPmiceseemedmoresusceptibletodisturbancebyLPSthantheBBBofHIV-1freecontrolanimals.
AnearlierinvitrostudybyothersfoundthatplacingLPS-stimulatedmacrophagesonanartificialBBBledtotheoccurrenceofgapsbetweenendothelialcellsandcausedasignificantincreaseinmonocytetransmigration[115].
Theactivatedmono-cytesreleasedTNF-α,IL-6andIL-10,butviralinfectionitselfsurprisinglydidnotincreasetransmigrationundertheseconditions,suggestingthattheLPSexertedadomi-nanteffect.
AmorerecentstudyfoundanalternatemechanismwhereLPSenhancedthetrans-cellulartrans-portofHIV-1acrosstheBBBviaap38MAPK-dependentpathway[116].
TryptophanmetabolismviathekynureninepathwayoccursinthehumanBBBduringHIV-1infectionandhasbeenlinkedtoimmunetoleranceandneurotoxicity[117].
EndothelialcellsandpericytesoftheBBB,aswellasastrocytes[118],acquireuponimmunestimulationthecapabilitytoproducekynurenine,whichwhenreleasedintothevicinityofmacrophagesandmicrogliacouldbefurthermetabolizedtotheneurotoxinquinolinicacid[119].
Ofnote,IFNsandLPSarebothabletoactivatetryptophancatabolisminmacrophages[120],aprocessthatmayaddtotheeffectsofBBBactivationduringHIVinfection.
Thus,peripheralHIV-1infectionandassoci-atedimmunestimulationsidebysidewithLPStransloca-tioncouldpotentiallyexertneurotoxicityacrosstheBBBevenwithoutthevirusenteringthebrain.
AdhesionMoleculesCellmigrationalsoengagesadhesionmolecules,andincreasedexpressionofvariousadhesionmolecules,suchasVCAM-1,hasbeenimplicatedinmononuclearcellmigrationintothebrainduringHIVandSIVinfection[80,115,121,122].
Astrocytesapparentlycontrolexpres-sionofICAM-1inendothelialcellsoftheBBB,anduponexposuretoTNF-α,producethemselvesICAM-1,VCAM-1,IG9andE-selectin,allofwhichmaypromotemonocyteattachmentandtransmigration[121].
HIV-infectedmacrophages,inparticularwhenaddi-tionallystimulatedwithLPS,induceexpressionofE-selectinandVCAM-1inbrainmicrovascularendothelialcells(BMEC)[80].
InbrainspecimensfromAIDSpatientswithHIVE,detectionofE-selectinandVCAM-1correlatedwithHIV-1andpro-inflammatorycytokines;andanassociationofinvadingmacrophagesandincreasedsignalforendothelialadhesionmoleculeswereobservedinHIVEsamples.
Possiblycounteractingtheeffectsofpro-inflammatorycytokines,theactivationofperoxisomeproliferator-acti-vatedreceptorγ(PPARγ)inHBMECscansuppresstheactivityofRhoGTPases(Rac1andRhoA)andinhibitadhesionandtransendothelialmigrationofHIV-1infectedmonocytes[123].
TightJunctionProteinsConcomitantwiththedevelopmentofHIVE,theexpres-sionoftightjunctionproteinsbetweenBMECsoftheBBBdecreases.
ThedisruptionoftightjunctionsbetweenBMECsisapparentlymediatedthroughtheactivationoffocaladhesionkinase(FAK)byphosphorylationatTYR-397[124].
Furthermore,HIV-1gp120seemscapableofinducingthedisruptionoftightjunctionsbytriggeringproteasomaldegradationofZO-1andZO-2inHBMEC[125].
Interestingly,thescaffoldingprotein14-3-3tauappearstocounteractthedown-regulationbyHIVgp120ofZO-1andZO-2;andevenmoresurprisingly,theviralenvelopeproteinspecificallyincreasesexpressionof14-3-3tau[125].
InadditiontoHIVgp120,Tatalsoaffectstightjunctionproteins[126].
AssuchTatreducestheexpressionofoccludin,ZO-1,andZO-2inthecaveolarcompartmentofHBMECs.
TheeffectofTatisdependentoncaveolin-1anditsmodulationofRassignaling.
DrugsofAbuseandAlcoholAbuseofpsycho-stimulatoryandaddictivedrugsseemstoincreasetheriskofHIV-1infectionandofthedevelop-mentofHAND[127-130].
HIVTatandmorphineapparentlycooperateindimin-ishingtheelectricalresistanceandincreasingthetrans-migrationacrosstheBBBviatheactivationofpro-inflammatorycytokines,thestimulationofintracellularCa2+release,andtheactivationofmyosinlightchainkinase[131].
Asimilareffectiscausedbybothmetham-phetamineandHIVgp120eitheraloneorincombination[132].
Cocainealsoalterstheexpressionoftightjunctionpro-teinsandinducesstressfibersinBMECs,anditinaddi-tionup-regulatesthepro-migratoryCCL2/CCR2ligand-GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page6of11receptorsystemthusfacilitatingthepassageofHIV-infectedmonocytesthroughtheBBB[133].
InaninvitroBBBmodelcomprisingendothelialcellsandastrocytes,cocainewasalsofoundtodecreasebarrierfunction,increaseexpressionofICAM-1,VCAM-1andplatelet-endothelialcelladhesionmolecule(PECAM)-1,andtoenhancemonocytemigrationacrosstheBBB[134].
Incontrasttothebefore-mentioneddrugs,cannabi-noidshavebeenreportedtopreserveinHBMECs,inthepresenceofHIVgp120,theexpressionoftightjunctionproteins.
CannabinoidsdecreasethepermeabilityoftheBBBandinhibitthetransmigrationofHIV-infectedmonocytesthroughthebarrier[135].
AlcoholandHIV-1gp120bothaffectBBBpermeabilityandstressfiberformationinBMECs[136].
Interestingly,alltheseeffectscanapparentlybeamelioratedbytheinhibitionofreactiveoxygenspecies[136].
GeneralconsiderationsandconclusionHIVenterstheCNSveryearlyafterinfection,andthenmaintainsitspresenceinthebrainthroughouttheindi-vidual'slife.
Interestingly,majoralterationsoftheBBBoccuronlylateinHIV-CNSdiseaseandthusinitialseed-inglikelyreflectsthehijackingofphysiologicalmecha-nismsofBBBcrossing,suchastheTrojanhorsestrategyinitiallyproposedbyNarayanandcolleagues[137,138].
Amodelofthemultistep,multifactorialprocessofCNSinvasionbyHIV-1,isillustratedinfigure1.
IthasforyearsremainedunclearwhethertheinfectedCNSconsti-tuted,afteritsinitialseeding,aviralsanctuaryindepen-dentoftheperipheryorjustreflectedinfectionfeaturesoutsidethebrain.
TheintroductionofHAARTchal-lengedourvisionofthebrainasanindependentsanctu-aryofHIVinfectionbecausethelowerincidenceofHADintreatedpatients,despitelowbrainpenetrationofthemolecules,stronglysuggestedthatHIVinducedCNSdis-ordersdorequirecontinuousimmuneactivationinthebrainandneuroinvasionofactivatedand/orinfectedleu-kocytes.
Thisinterdependenceisexemplifiedbythefactthat,inhumansandinanimalmodels,neurologicalcomplica-tionsofHIVinfectioncorrelatenotonlywithinnateimmunity[35]andmacrophage/microgliaactivation[11,18,24]withinthebraintissue,butalsowithproviralloadinactivatedperipheralCD16+monocytes/mac-rophages[29,40,41].
Inthiscontext,BBBcrossingbyHIVFigure1MechanisticmodelofHIV-1neuroinvasion.
(1)Thephysiologicalexpressionofchemokinesbybraincells,amongwhicharesolublefrac-talkine(Fkn)andCXCL12,supportsaslowbutcontinuousentryofmonocytesandmacrophagesintothecentralnervoussystem.
Duetotheirexpres-sionofCX3CR1,CD16positive,activatedmonocytesarethepreferentialtargetsforsuchattraction.
TheseCD16positivemonocytesarethemainreservoirofmonocyte/macrophage-harboredvirusandarethuslikelytobethepredominantcelltypecarryingHIVintothebrain.
(2)InfiltratedHIV-infectedmonocyteslocallyproduceHIVandinflammatorymediatorsinperivascularareas.
Thisactivatesneighbouringastrocytesaswellasthebloodbrainbarrier(BBB)endothelium.
(3)Inresponse,endothelialcellsup-regulateadhesionmolecules,enhancingmonocyterecruitment.
However,mem-brane-boundFknisalsoinducedonendothelialcellsandcanarrestCD16positivemonocytesattheendotheliumthusinhibitingtheirfurtherinfiltra-tion.
(4)CCL2isoverexpressedbyinfected,HIV-stimulatedmacrophagesandactivatedastrocytes,attractingCD16negative,CCR2positivemonocytestowardtheperivasculararea.
(5)BothCXCL12andnervegrowthfactor(NGF)areoverexpressedintheinflamedbrain.
NGFincreasesCXCR4expres-sionandpromotesuninfectedmonocyteattractionbyCXCL12.
Atthesametimeitlimitsentryofinfectedmonocytesintothebrain.
(6)ActivateduninfectedperivascularmacrophagesmaybetargetsfordenovoinfectionbylocallyproducedHIV,amplifyingtheactivation-attraction-infectioncycle.
(7)LocalinflammationaswellasHIVproductsinducetightjunctiondisorganizationandleadtobreachesintheBBB.
Toxicserumproteinsandfreevirionsmayenterthebrain,favouringmoreinfectionandfurtheramplifyinginflammation.
CD16+MonocyteAstrocyteCD16-MonocyteBreachedBBBPerivascularmacrophageBloodstreamBraintissue1234657CD16CX3CR1CXCR4CCR2TrkAand/orp75NTRTightjunctionAdhesionmoleculesSolubleFKNMembrane-boundFKNCXCL12CCL2HIVvirionNGF45GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page7of11infectedandimmune-activatedmacrophagesappearstobeacriticaltargetforfuturetherapeuticdevelopments.
Theverycomplexandintricatemechanismsthatgovernthiscrossingshouldthusbestudiedwithparticularatten-tion.
HANDcorrelatewithCSFviralload[25],whichiscloselyrelatedtoCSFpleocytosis[139].
Inarecentstudy,Sinclairetal.
showedthatHAARTdespitetreatmentfail-ureswithnoeffectonperipheralviralload,hadneverthe-lessasignificantbeneficialimpactonCSFviralload,CSFpleocytosis,andimmuneactivation[140].
ThisstrikingandencouragingresultfurtherillustratesthecriticalimportanceofanimprovedunderstandingofBBBfunc-tionandneuroinvasionmechanisms.
Furthermore,HIVneuroinvasionandBBBlikelywillprovidefuturethera-peutictargetsforcopingwiththeanticipatedincreaseinHANDprevalenceasmoreandmoreHIVpatientscomeofage.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsGGandMKwrotethearticlejointly.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsThisreviewwasinspiredbydiscussionsoftheroleofthecellsofthemononu-clearphagocytelineageinHIVinfectionduringmeetingsconductedbytheAssociationforMacrophageinInfectionResearch(AMIR).
ArticleprocessingchargesofthisreviewarepaidforbytheConcertedAction31-Dendriticcells,AntigenPresentationandInnateImmunityofthe"AgenceNationaledeRecherchesurleSidaetlesHépatitesVirales"(ANRS).
M.
KaulwassupportedbyNIHgrantR01NS050621.
G.
Graswassupportedbygrantsfromthe"AgenceNationaledeRecherchesurleSidaetlesHépatitesVirales"(ANRS),theFonda-tionpourlaRechercheMédicale(FRM)andEnsembleContreleSida(SIDACTION).
AuthorDetails1InstituteofEmergingDiseasesandInnovativeTherapies,DivisionofImmuno-Virology,CEA,18RouteduPanorama,F92265Fontenay-auxRoses,Franceand2Infectious&InflammatoryDiseaseCenter,BurnhamInstituteforMedicalResearch,10901NorthTorreyPinesRoad,LaJolla,CA92037,USAReferences1.
AntinoriA,ArendtG,BeckerJT,BrewBJ,ByrdDA,ChernerM,CliffordDB,CinqueP,EpsteinLG,GoodkinK,GisslenM,GrantI,HeatonRK,JosephJ,MarderK,MarraCM,McArthurJC,NunnM,PriceRW,PulliamL,RobertsonKR,SacktorN,ValcourV,WojnaVE:UpdatedresearchnosologyforHIV-associatedneurocognitivedisorders.
Neurology2007,69:1789-1799.
2.
GhafouriM,AminiS,KhaliliK,SawayaBE:HIV-1associateddementia:symptomsandcauses.
Retrovirology2006,3:28.
3.
McArthurJC,HooverDR,BacellarH,MillerEN,CohenBA,BeckerJT,GrahamNM,McArthurJH,SelnesOA,JacobsonLP,etal.
:DementiainAIDSpatients:incidenceandriskfactors.
MulticenterAIDSCohortStudy.
Neurology1993,43:2245-2252.
4.
EllisRJ,DeutschR,HeatonRK,MarcotteTD,McCutchanJA,NelsonJA,AbramsonI,ThalLJ,AtkinsonJH,WallaceMR,GrantI:NeurocognitiveimpairmentisanindependentriskfactorfordeathinHIVinfection.
SanDiegoHIVNeurobehavioralResearchCenterGroup.
ArchNeurol1997,54:416-424.
5.
LinerKJ,HallCD,RobertsonKR:Effectsofantiretroviraltherapyoncognitiveimpairment.
CurrHIV/AIDSRep2008,5:64-71.
6.
BoisseL,GillMJ,PowerC:HIVinfectionofthecentralnervoussystem:clinicalfeaturesandneuropathogenesis.
NeurolClin2008,26:799-819.
x7.
BrewBJ,CroweSM,LandayA,CysiqueLA,GuilleminG:NeurodegenerationandageingintheHAARTera.
JNeuroimmunePharmacol2009,4:163-174.
8.
LetendreS,Marquie-BeckJ,CapparelliE,BestB,CliffordD,CollierAC,GelmanBB,McArthurJC,McCutchanJA,MorgelloS,SimpsonD,GrantI,EllisRJ,CHARTERGroup:ValidationoftheCNSPenetration-Effectivenessrankforquantifyingantiretroviralpenetrationintothecentralnervoussystem.
ArchNeurol2008,65:65-70.
9.
Adle-BiassetteH,BellJE,CreangeA,SazdovitchV,AuthierFJ,GrayF,HauwJJ,GherardiR:DNAbreaksdetectedbyinsituend-labellingindorsalrootgangliaofpatientswithAIDS.
NeuropatholApplNeurobiol1998,24:373-380.
10.
MasliahE,HeatonRK,MarcotteTD,EllisRJ,WileyCA,MalloryM,AchimCL,McCutchanJA,NelsonJA,AtkinsonJH,GrantI:Dendriticinjuryisapathologicalsubstrateforhumanimmunodeficiencyvirus-relatedcognitivedisorders.
HNRCGroup.
TheHIVNeurobehavioralResearchCenter.
AnnNeurol1997,42:963-972.
11.
PetitoCK,ChoES,LemannW,NaviaBA,PriceRW:Neuropathologyofacquiredimmunodeficiencysyndrome(AIDS):anautopsyreview.
JNeuropatholExpNeurol1986,45:635-646.
12.
EverallIP,LuthertPJ,LantosPL:NeuronallossinthefrontalcortexinHIVinfection.
Lancet1991,337:1119-1121.
13.
KetzlerS,WeisS,HaugH,BudkaH:LossofneuronsinthefrontalcortexinAIDSbrains.
ActaNeuropathol1990,80:92-94.
14.
ReyesMG,FaraldiF,SensengCS,FlowersC,FarielloR:Nigraldegenerationinacquiredimmunedeficiencysyndrome(AIDS).
ActaNeuropathol1991,82:39-44.
15.
GrausF,RibaltaT,AbosJ,AlomJ,Cruz-SanchezF,MallolasJ,MiroJM,CardesaA,TolosaE:SubacutecerebellarsyndromeasthefirstmanifestationofAIDSdementiacomplex.
ActaNeurolScand1990,81:118-120.
16.
EverallI,LuthertP,LantosP:Areviewofneuronaldamageinhumanimmunodeficiencyvirusinfection:itsassessment,possiblemechanismandrelationshiptodementia.
JNeuropatholExpNeurol1993,52:561-566.
17.
AnthonyIC,BellJE:TheNeuropathologyofHIV/AIDS.
IntRevPsychiatry2008,20:15-24.
18.
GlassJD,FedorH,WesselinghSL,McArthurJC:Immunocytochemicalquantitationofhumanimmunodeficiencyvirusinthebrain:correlationswithdementia.
AnnNeurol1995,38:755-762.
19.
LangfordTD,LetendreSL,LarreaGJ,MasliahE:ChangingpatternsintheneuropathogenesisofHIVduringtheHAARTera.
BrainPathol2003,13:195-210.
20.
HoDD,RotaTR,SchooleyRT,KaplanJC,AllanJD,GroopmanJE,ResnickL,FelsensteinD,AndrewsCA,HirschMS:IsolationofHTLV-IIIfromcerebrospinalfluidandneuraltissuesofpatientswithneurologicsyndromesrelatedtotheacquiredimmunodeficiencysyndrome.
NEnglJMed1985,313:1493-1497.
21.
KoenigS,GendelmanHE,OrensteinJM,DalCantoMC,PezeshkpourGH,YungbluthM,JanottaF,AksamitA,MartinMA,FauciAS:DetectionofAIDSvirusinmacrophagesinbraintissuefromAIDSpatientswithencephalopathy.
Science1986,233:1089-1093.
22.
AsensioVC,CampbellIL:ChemokinesintheCNS:plurifunctionalmediatorsindiversestates.
TrendsNeurosci1999,22:504-512.
23.
SadagopalS,LoreySL,BarnettL,BashamR,LeboL,ErdemH,HamanK,AvisonM,WaddellK,HaasDW,KalamsSA:Enhancementofhumanimmunodeficiencyvirus(HIV)-specificCD8+Tcellsincerebrospinalfluidcomparedtothoseinbloodamongantiretroviraltherapy-naiveHIV-positivesubjects.
JVirol2008,82:10418-10428.
24.
AnthonyIC,RamageSN,CarnieFW,SimmondsP,BellJE:InfluenceofHAARTonHIV-relatedCNSdiseaseandneuroinflammation.
JNeuropatholExpNeurol2005,64:529-536.
25.
BrewBJ,PembertonL,CunninghamP,LawMG:Levelsofhumanimmunodeficiencyvirustype1RNAincerebrospinalfluidcorrelatewithAIDSdementiastage.
JInfectDis1997,175:963-966.
26.
EllisRJ,HsiaK,SpectorSA,NelsonJA,HeatonRK,WallaceMR,AbramsonI,AtkinsonJH,GrantI,McCutchanJA:Cerebrospinalfluidhumanimmunodeficiencyvirustype1RNAlevelsareelevatedinReceived:1October2009Accepted:7April2010Published:7April2010Thisarticleisavailablefrom:http://www.
retrovirology.
com/content/7/1/302010GrasandKaul;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Retrovirology2010,7:30GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page8of11neurocognitivelyimpairedindividualswithacquiredimmunodeficiencysyndrome.
HIVNeurobehavioralResearchCenterGroup.
AnnNeurol1997,42:679-688.
27.
McArthurJC,McClernonDR,CroninMF,Nance-SprosonTE,SaahAJ,StClairM,LanierER:Relationshipbetweenhumanimmunodeficiencyvirus-associateddementiaandviralloadincerebrospinalfluidandbrain.
AnnNeurol1997,42:689-698.
28.
WileyCA,SoontornniyomkijV,RadhakrishnanL,MasliahE,MellorsJ,HermannSA,DaileyP,AchimCL:DistributionofbrainHIVloadinAIDS.
BrainPathol1998,8:277-284.
29.
GartnerS:HIVinfectionanddementia.
Science2000,287:602-604.
30.
BanksWA,ErcalN,PriceTO:Theblood-brainbarrierinneuroAIDS.
CurrHIVRes2006,4:259-266.
31.
ChoYY,AstgenA,HendelH,IssingW,PerrotJY,SchachterF,RappaportJ,ZaguryJF:Homeostasisofchemokines,interferonproductionandlymphocytesubsets:implicationsforAIDSpathogenesis.
BiomedPharmacother1997,51:221-229.
32.
MandlJN,BarryAP,VanderfordTH,KozyrN,ChavanR,KluckingS,BarratFJ,CoffmanRL,StapransSI,FeinbergMB:DivergentTLR7andTLR9signalingandtypeIinterferonproductiondistinguishpathogenicandnonpathogenicAIDSvirusinfections.
NatMed2008,14:1077-1087.
33.
PoliG,BiswasP,FauciAS:Interferonsinthepathogenesisandtreatmentofhumanimmunodeficiencyvirusinfection.
AntiviralRes1994,24:221-233.
34.
SasAR,Bimonte-NelsonH,SmothersCT,WoodwardJ,TyorWR:Interferon-alphacausesneuronaldysfunctioninencephalitis.
JNeurosci2009,29:3948-3955.
35.
SasAR,Bimonte-NelsonHA,TyorWR:CognitivedysfunctioninHIVencephaliticSCIDmicecorrelateswithlevelsofInterferon-alphainthebrain.
Aids2007,21:2151-2159.
36.
ArgyrisEG,AcheampongE,WangF,HuangJ,ChenK,MukhtarM,ZhangH:Theinterferon-inducedexpressionofAPOBEC3Ginhumanblood-brainbarrierexertsapotentintrinsicimmunitytoblockHIV-1entrytocentralnervoussystem.
Virology2007,367:440-451.
37.
ThieblemontN,WeissL,SadeghiHM,EstcourtC,Haeffner-CavaillonN:CD14lowCD16high:acytokine-producingmonocytesubsetwhichexpandsduringhumanimmunodeficiencyvirusinfection.
EurJImmunol1995,25:3418-3424.
38.
PulliamL,GasconR,StubblebineM,McGuireD,McGrathMS:UniquemonocytesubsetinpatientswithAIDSdementia.
Lancet1997,349:692-695.
39.
ColemanCM,WuL:HIVinteractionswithmonocytesanddendriticcells:virallatencyandreservoirs.
Retrovirology2009,6:51.
40.
ElleryPJ,TippettE,ChiuYL,PaukovicsG,CameronPU,SolomonA,LewinSR,GorryPR,JaworowskiA,GreeneWC,SonzaS,CroweSM:TheCD16+monocytesubsetismorepermissivetoinfectionandpreferentiallyharborsHIV-1invivo.
JImmunol2007,178:6581-6589.
41.
ShiramizuB,GartnerS,WilliamsA,ShikumaC,Ratto-KimS,WattersM,AguonJ,ValcourV:CirculatingproviralHIVDNAandHIV-associateddementia.
Aids2005,19:45-52.
42.
KalterDC,NakamuraM,TurpinJA,BacaLM,HooverDL,DieffenbachC,RalphP,GendelmanHE,MeltzerMS:EnhancedHIVreplicationinmacrophagecolony-stimulatingfactor-treatedmonocytes.
JImmunol1991,146:298-306.
43.
NaifHM,LiS,AlaliM,SloaneA,WuL,KellyM,LynchG,LloydA,CunninghamAL:CCR5expressioncorrelateswithsusceptibilityofmaturingmonocytestohumanimmunodeficiencyvirustype1infection.
JVirol1998,72:830-836.
44.
RichEA,ChenIS,ZackJA,LeonardML,O'BrienWA:Increasedsusceptibilityofdifferentiatedmononuclearphagocytestoproductiveinfectionwithhumanimmunodeficiencyvirus-1(HIV-1).
JClinInvest1992,89:176-183.
45.
SchrierRD,FreemanWR,WileyCA,McCutchanJA:CMV-specificimmuneresponsesandHLAphenotypesofAIDSpatientswhodevelopCMVretinitis.
HNRCGroup.
HIVNeurobehavioralResearchCenter.
AdvNeuroimmunol1994,4:327-336.
46.
SchrierRD,McCutchanJA,WileyCA:Mechanismsofimmuneactivationofhumanimmunodeficiencyvirusinmonocytes/macrophages.
JVirol1993,67:5713-5720.
47.
SonzaS,MaerzA,DeaconN,MeangerJ,MillsJ,CroweS:Humanimmunodeficiencyvirustype1replicationisblockedpriortoreversetranscriptionandintegrationinfreshlyisolatedperipheralbloodmonocytes.
JVirol1996,70:3863-3869.
48.
WangX,YeL,HouW,ZhouY,WangYJ,MetzgerDS,HoWZ:CellularmicroRNAexpressioncorrelateswithsusceptibilityofmonocytes/macrophagestoHIV-1infection.
Blood2009,113:671-674.
49.
AncutaP,KunstmanKJ,AutissierP,ZamanT,StoneD,WolinskySM,GabuzdaD:CD16+monocytesexposedtoHIVpromotehighlyefficientviralreplicationupondifferentiationintomacrophagesandinteractionwithTcells.
Virology2006,344:267-276.
50.
AncutaP,LiuKY,MisraV,WaclecheVS,GosselinA,ZhouX,GabuzdaD:TranscriptionalprofilingrevealsdevelopmentalrelationshipanddistinctbiologicalfunctionsofCD16+andCD16-monocytesubsets.
BMCGenomics2009,10:403.
51.
AncutaP,MosesA,GabuzdaD:TransendothelialmigrationofCD16+monocytesinresponsetofractalkineunderconstitutiveandinflammatoryconditions.
Immunobiology2004,209:11-20.
52.
AncutaP,RaoR,MosesA,MehleA,ShawSK,LuscinskasFW,GabuzdaD:FractalkinepreferentiallymediatesarrestandmigrationofCD16+monocytes.
JExpMed2003,197:1701-1707.
53.
Fischer-SmithT,BellC,CroulS,LewisM,RappaportJ:Monocyte/macrophagetraffickinginacquiredimmunodeficiencysyndromeencephalitis:lessonsfromhumanandnonhumanprimatestudies.
JNeurovirol2008,14:318-326.
54.
GartnerS,MarkovitsP,MarkovitzDM,BettsRF,PopovicM:VirusisolationfromandidentificationofHTLV-III/LAV-producingcellsinbraintissuefromapatientwithAIDS.
Jama1986,256:2365-2371.
55.
GartnerS,MarkovitsP,MarkovitzDM,KaplanMH,GalloRC,PopovicM:TheroleofmononuclearphagocytesinHTLV-III/LAVinfection.
Science1986,233:215-219.
56.
EmbretsonJ,ZupancicM,RibasJL,BurkeA,RaczP,Tenner-RaczK,HaaseAT:MassivecovertinfectionofhelperTlymphocytesandmacrophagesbyHIVduringtheincubationperiodofAIDS.
Nature1993,362:359-362.
57.
MartinJC,BandresJC:Cellsofthemonocyte-macrophagelineageandpathogenesisofHIV-1infection.
JAcquirImmuneDeficSyndr1999,22:413-429.
58.
OrensteinJM,FoxC,WahlSM:MacrophagesasasourceofHIVduringopportunisticinfections.
Science1997,276:1857-1861.
59.
AlkhatibG,CombadiereC,BroderCC,FengY,KennedyPE,MurphyPM,BergerEA:CCCKR5:aRANTES,MIP-1alpha,MIP-1betareceptorasafusioncofactorformacrophage-tropicHIV-1.
Science1996,272:1955-1958.
60.
ChoeH,FarzanM,SunY,SullivanN,RollinsB,PonathPD,WuL,MackayCR,LaRosaG,NewmanW,GerardN,GerardC,SodroskiJ:Thebeta-chemokinereceptorsCCR3andCCR5facilitateinfectionbyprimaryHIV-1isolates.
Cell1996,85:1135-1148.
61.
DragicT,LitwinV,AllawayGP,MartinSR,HuangY,NagashimaKA,CayananC,MaddonPJ,KoupRA,MooreJP,PaxtonWA:HIV-1entryintoCD4+cellsismediatedbythechemokinereceptorCC-CKR-5.
Nature1996,381:667-673.
62.
AlbrightAV,ShiehJT,ItohT,LeeB,PleasureD,O'ConnorMJ,DomsRW,Gonzalez-ScaranoF:MicrogliaexpressCCR5,CXCR4,andCCR3,butofthese,CCR5istheprincipalcoreceptorforhumanimmunodeficiencyvirustype1dementiaisolates.
JVirol1999,73:205-213.
63.
HeJ,ChenY,FarzanM,ChoeH,OhagenA,GartnerS,BusciglioJ,YangX,HofmannW,NewmanW,MackayCR,SodroskiJ,GabuzdaD:CCR3andCCR5areco-receptorsforHIV-1infectionofmicroglia.
Nature1997,385:645-649.
64.
LiS,JuarezJ,AlaliM,DwyerD,CollmanR,CunninghamA,NaifHM:PersistentCCR5utilizationandenhancedmacrophagetropismbyprimarybloodhumanimmunodeficiencyvirustype1isolatesfromadvancedstagesofdiseaseandcomparisontotissue-derivedisolates.
JVirol1999,73:9741-9755.
65.
ShiehJT,AlbrightAV,SharronM,GartnerS,StrizkiJ,DomsRW,Gonzalez-ScaranoF:Chemokinereceptorutilizationbyhumanimmunodeficiencyvirustype1isolatesthatreplicateinmicroglia.
JVirol1998,72:4243-4249.
66.
SmitTK,WangB,NgT,OsborneR,BrewB,SaksenaNK:VariedtropismofHIV-1isolatesderivedfromdifferentregionsofadultbraincortexdiscriminatebetweenpatientswithandwithoutAIDSdementiacomplex(ADC):evidenceforneurotropicHIVvariants.
Virology2001,279:509-526.
GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page9of1167.
GorryPR,BristolG,ZackJA,RitolaK,SwanstromR,BirchCJ,BellJE,BannertN,CrawfordK,WangH,ScholsD,DeClercqE,KunstmanK,WolinskySM,GabuzdaD:Macrophagetropismofhumanimmunodeficiencyvirustype1isolatesfrombrainandlymphoidtissuespredictsneurotropismindependentofcoreceptorspecificity.
JVirol2001,75:10073-10089.
68.
GorryPR,TaylorJ,HolmGH,MehleA,MorganT,CayabyabM,FarzanM,WangH,BellJE,KunstmanK,MooreJP,WolinskySM,GabuzdaD:IncreasedCCR5affinityandreducedCCR5/CD4dependenceofaneurovirulentprimaryhumanimmunodeficiencyvirustype1isolate.
JVirol2002,76:6277-6292.
69.
GrayL,RocheM,ChurchillMJ,SterjovskiJ,EllettA,PoumbouriosP,SherieffS,WangB,SaksenaN,PurcellDF,WesselinghS,CunninghamAL,BrewBJ,GabuzdaD,GorryPR:Tissue-specificsequencealterationsinthehumanimmunodeficiencyvirustype1envelopefavoringCCR5usagecontributetopersistenceofdual-tropicvirusinthebrain.
JVirol2009,83:5430-5441.
70.
ClayCC,RodriguesDS,HoYS,FallertBA,JanatpourK,ReinhartTA,EsserU:Neuroinvasionoffluorescein-positivemonocytesinacutesimianimmunodeficiencyvirusinfection.
JVirol2007,81:12040-12048.
71.
FialaM,LooneyDJ,StinsM,WayDD,ZhangL,GanX,ChiappelliF,SchweitzerES,ShapshakP,WeinandM,GravesMC,WitteM,KimKS:TNF-alphaopensaparacellularrouteforHIV-1invasionacrosstheblood-brainbarrier.
MolMed1997,3:553-564.
72.
FletcherNF,BexigaMG,BraydenDJ,BrankinB,WillettBJ,HosieMJ,JacqueJM,CallananJJ:Lymphocytemigrationthroughthebloodbrainbarrier(BBB)infelineimmunodeficiencyvirusinfectionissignificantlyinfluencedbythepre-existenceofvirusandTNF-alphawithintheCNS:studiesusinganinvitrofelineBBBmodel.
NeuropatholApplNeurobiol2009,36:592-602.
73.
AncutaP,KamatA,KunstmanKJ,KimEY,AutissierP,WurcelA,ZamanT,StoneD,MeffordM,MorgelloS,SingerEJ,WolinskySM,GabuzdaD:MicrobialtranslocationisassociatedwithincreasedmonocyteactivationanddementiainAIDSpatients.
PLoSOne2008,3:e2516.
74.
BrenchleyJM,PriceDA,DouekDC:HIVdisease:falloutfromamucosalcatastropheNatImmunol2006,7:235-239.
75.
BrenchleyJM,PriceDA,SchackerTW,AsherTE,SilvestriG,RaoS,KazzazZ,BornsteinE,LambotteO,AltmannD,BlazarBR,RodriguezB,Teixeira-JohnsonL,LandayA,MartinJN,HechtFM,PickerLJ,LedermanMM,DeeksSG,DouekDC:MicrobialtranslocationisacauseofsystemicimmuneactivationinchronicHIVinfection.
NatMed2006,12:1365-1371.
76.
WangH,SunJ,GoldsteinH:Humanimmunodeficiencyvirustype1infectionincreasestheinvivocapacityofperipheralmonocytestocrosstheblood-brainbarrierintothebrainandtheinvivosensitivityoftheblood-brainbarriertodisruptionbylipopolysaccharide.
JVirol2008,82:7591-7600.
77.
BazanJF,BaconKB,HardimanG,WangW,SooK,RossiD,GreavesDR,ZlotnikA,SchallTJ:Anewclassofmembrane-boundchemokinewithaCX3Cmotif.
Nature1997,385:640-644.
78.
KaulM,GardenGA,LiptonSA:PathwaystoneuronalinjuryandapoptosisinHIV-associateddementia.
Nature2001,410:988-994.
79.
PowerC,McArthurJC,NathA,WehrlyK,MayneM,NishioJ,LangelierT,JohnsonRT,ChesebroB:Neuronaldeathinducedbybrain-derivedhumanimmunodeficiencyvirustype1envelopegenesdiffersbetweendementedandnondementedAIDSpatients.
JVirol1998,72:9045-9053.
80.
NottetHS,PersidskyY,SassevilleVG,NukunaAN,BockP,ZhaiQH,SharerLR,McCombRD,SwindellsS,SoderlandC,GendelmanHE:MechanismsforthetransendothelialmigrationofHIV-1-infectedmonocytesintobrain.
JImmunol1996,156:1284-1295.
81.
GrayF,BelecL,ChretienF,Dubreuil-LemaireML,RicolfiF,WingertsmannL,PoronF,GherardiR:Acute,relapsingbrainoedemawithdiffuseblood-brainbarrieralterationandaxonaldamageintheacquiredimmunodeficiencysyndrome.
NeuropatholApplNeurobiol1998,24:209-216.
82.
PetitoCK,CashKS:Blood-brainbarrierabnormalitiesintheacquiredimmunodeficiencysyndrome:immunohistochemicallocalizationofserumproteinsinpostmortembrain.
AnnNeurol1992,32:658-666.
83.
MacleanAG,BelenchiaGE,BieniemyDN,Moroney-RasmussenTA,LacknerAA:Simianimmunodeficiencyvirusdisruptsextendedlengthsoftheblood--brainbarrier.
JMedPrimatol2005,34:237-242.
84.
DallastaLM,PisarovLA,EsplenJE,WerleyJV,MosesAV,NelsonJA,AchimCL:Blood-brainbarriertightjunctiondisruptioninhumanimmunodeficiencyvirus-1encephalitis.
AmJPathol1999,155:1915-1927.
85.
PersidskyY,HeilmanD,HaorahJ,ZelivyanskayaM,PersidskyR,WeberGA,ShimokawaH,KaibuchiK,IkezuT:Rho-mediatedregulationoftightjunctionsduringmonocytemigrationacrosstheblood-brainbarrierinHIV-1encephalitis(HIVE).
Blood2006,107:4770-4780.
86.
LuabeyaMK,DallastaLM,AchimCL,PauzaCD,HamiltonRL:Blood-brainbarrierdisruptioninsimianimmunodeficiencyvirusencephalitis.
NeuropatholApplNeurobiol2000,26:454-462.
87.
MankowskiJL,QueenSE,KirsteinLM,SpelmanJP,LaterraJ,SimpsonIA,AdamsRJ,ClementsJE,ZinkMC:Alterationsinblood-brainbarrierglucosetransportinSIV-infectedmacaques.
JNeurovirol1999,5:695-702.
88.
KhanNA,DiCelloF,StinsM,KimKS:Gp120-mediatedcytotoxicityofhumanbrainmicrovascularendothelialcellsisdependentonp38mitogen-activatedproteinkinaseactivation.
JNeurovirol2007,13:242-251.
89.
MarshallDC,Wyss-CorayT,AbrahamCR:Inductionofmatrixmetalloproteinase-2inhumanimmunodeficiencyvirus-1glycoprotein120transgenicmousebrains.
NeurosciLett1998,254:97-100.
90.
BoehmeSA,LioFM,Maciejewski-LenoirD,BaconKB,ConlonPJ:ThechemokinefractalkineinhibitsFas-mediatedcelldeathofbrainmicroglia.
JImmunol2000,165:397-403.
91.
GonzalezE,RovinBH,SenL,CookeG,DhandaR,MummidiS,KulkarniH,BamshadMJ,TellesV,AndersonSA,WalterEA,StephanKT,DeucherM,ManganoA,BolognaR,AhujaSS,DolanMJ,AhujaSK:HIV-1infectionandAIDSdementiaareinfluencedbyamutantMCP-1allelelinkedtoincreasedmonocyteinfiltrationoftissuesandMCP-1levels.
ProcNatlAcadSciUSA2002,99:13795-13800.
92.
El-HageN,WuG,AmbatiJ,Bruce-KellerAJ,KnappPE,HauserKF:CCR2mediatesincreasesinglialactivationcausedbyexposuretoHIV-1Tatandopiates.
JNeuroimmunol2006,178:9-16.
93.
El-HageN,WuG,WangJ,AmbatiJ,KnappPE,ReedJL,Bruce-KellerAJ,HauserKF:HIV-1Tatandopiate-inducedchangesinastrocytespromotechemotaxisofmicrogliathroughtheexpressionofMCP-1andalternativechemokines.
Glia2006,53:132-146.
94.
EugeninEA,OsieckiK,LopezL,GoldsteinH,CalderonTM,BermanJW:CCL2/monocytechemoattractantprotein-1mediatesenhancedtransmigrationofhumanimmunodeficiencyvirus(HIV)-infectedleukocytesacrosstheblood-brainbarrier:apotentialmechanismofHIV-CNSinvasionandNeuroAIDS.
JNeurosci2006,26:1098-1106.
95.
GuL,RutledgeB,FiorilloJ,ErnstC,GrewalI,FlavellR,GladueR,RollinsB:Invivopropertiesofmonocytechemoattractantprotein-1.
JLeukocBiol1997,62:577-580.
96.
CinqueP,VagoL,MengozziM,TorriV,CeresaD,VicenziE,TransidicoP,VaganiA,SozzaniS,MantovaniA,LazzarinA,PoliG:Elevatedcerebrospinalfluidlevelsofmonocytechemotacticprotein-1correlatewithHIV-1encephalitisandlocalviralreplication.
Aids1998,12:1327-1332.
97.
ConantK,Garzino-DemoA,NathA,McArthurJC,HallidayW,PowerC,GalloRC,MajorEO:Inductionofmonocytechemoattractantprotein-1inHIV-1Tat-stimulatedastrocytesandelevationinAIDSdementia.
ProcNatlAcadSciUSA1998,95:3117-3121.
98.
KelderW,McArthurJC,Nance-SprosonT,McClernonD,GriffinDE:Beta-chemokinesMCP-1andRANTESareselectivelyincreasedincerebrospinalfluidofpatientswithhumanimmunodeficiencyvirus-associateddementia.
AnnNeurol1998,44:831-835.
99.
SozzaniS,IntronaM,BernasconiS,PolentaruttiN,CinqueP,PoliG,SicaA,MantovaniA:MCP-1andCCR2inHIVinfection:regulationofagonistandreceptorexpression.
JLeukocBiol1997,62:30-33.
100.
ZinkMC,ColemanGD,MankowskiJL,AdamsRJ,TarwaterPM,FoxK,ClementsJE:Increasedmacrophagechemoattractantprotein-1incerebrospinalfluidprecedesandpredictssimianimmunodeficiencyvirusencephalitis.
JInfectDis2001,184:1015-1021.
101.
SandersVJ,PittmanCA,WhiteMG,WangG,WileyCA,AchimCL:ChemokinesandreceptorsinHIVencephalitis.
Aids1998,12:1021-1026.
102.
BuchS,SuiY,PotulaR,PinsonD,AdanyI,LiZ,HuangM,LiS,DhillonN,MajorE,NarayanO:Roleofinterleukin-4andmonocytechemoattractantprotein-1intheneuropathogenesisofX4simianhumanimmunodeficiencyvirusinfectioninmacaques.
JNeurovirol2004,10(Suppl1):118-124.
GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page10of11103.
HicksA,PotulaR,SuiYJ,VillingerF,PinsonD,AdanyI,LiZ,LongC,CheneyP,MarcarioJ,NovembreF,MuellerN,KumarA,MajorE,NarayanO,BuchS:Neuropathogenesisoflentiviralinfectioninmacaques:rolesofCXCR4andCCR5virusesandinterleukin-4inenhancingmonocytechemoattractantprotein-1productioninmacrophages.
AmJPathol2002,161:813-822.
104.
PersidskyY,GhorpadeA,RasmussenJ,LimogesJ,LiuXJ,StinsM,FialaM,WayD,KimKS,WitteMH,WeinandM,CarhartL,GendelmanHE:Microglialandastrocytechemokinesregulatemonocytemigrationthroughtheblood-brainbarrierinhumanimmunodeficiencyvirus-1encephalitis.
AmJPathol1999,155:1599-1611.
105.
MalikM,ChenYY,KienzleMF,TomkowiczBE,CollmanRG,PtasznikA:MonocytemigrationandLFA-1-mediatedattachmenttobrainmicrovascularendotheliaisregulatedbySDF-1alphathroughLynkinase.
JImmunol2008,181:4632-4637.
106.
SamahB,PorcherayF,GrasG:Neurotrophinsmodulatemonocytechemotaxiswithoutaffectingmacrophagefunction.
ClinExpImmunol2008,151:476-486.
107.
SamahB,PorcherayF,Dereuddre-BosquetN,GrasG:NervegrowthfactorstimulationpromotesCXCL-12attractionofmonocytesbutdecreaseshumanimmunodeficiencyvirusreplicationinattractedpopulation.
JNeurovirol2009,15:71-80.
108.
WuDT,WoodmanSE,WeissJM,McManusCM,D'AversaTG,HesselgesserJ,MajorEO,NathA,BermanJW:MechanismsofleukocytetraffickingintotheCNS.
JNeurovirol2000,6(Suppl1):S82-85.
109.
GendelmanHE,DingS,GongN,LiuJ,RamirezSH,PersidskyY,MosleyRL,WangT,VolskyDJ,XiongH:Monocytechemotacticprotein-1regulatesvoltage-gatedK+channelsandmacrophagetransmigration.
JNeuroimmunePharmacol2009,4:47-59.
110.
ChaudhuriA,DuanF,MorseyB,PersidskyY,KanmogneGD:HIV-1activatesproinflammatoryandinterferon-induciblegenesinhumanbrainmicrovascularendothelialcells:putativemechanismsofblood-brainbarrierdysfunction.
JCerebBloodFlowMetab2008,28:697-711.
111.
YangB,AkhterS,ChaudhuriA,KanmogneGD:HIV-1gp120inducescytokineexpression,leukocyteadhesion,andtransmigrationacrosstheblood-brainbarrier:modulatoryeffectsofSTAT1signaling.
MicrovascRes2009,77:212-219.
112.
ChaudhuriA,YangB,GendelmanHE,PersidskyY,KanmogneGD:STAT1signalingmodulatesHIV-1-inducedinflammatoryresponsesandleukocytetransmigrationacrosstheblood-brainbarrier.
Blood2008,111:2062-2072.
113.
KanmogneGD,SchallK,LeibhartJ,KnipeB,GendelmanHE,PersidskyY:HIV-1gp120compromisesblood-brainbarrierintegrityandenhancesmonocytemigrationacrossblood-brainbarrier:implicationforviralneuropathogenesis.
JCerebBloodFlowMetab2007,27:123-134.
114.
Ricardo-DukelowM,KadiuI,RozekW,SchlautmanJ,PersidskyY,CiborowskiP,KanmogneGD,GendelmanHE:HIV-1infectedmonocyte-derivedmacrophagesaffectthehumanbrainmicrovascularendothelialcellproteome:newinsightsintoblood-brainbarrierdysfunctionforHIV-1-associateddementia.
JNeuroimmunol2007,185:37-46.
115.
PersidskyY,StinsM,WayD,WitteMH,WeinandM,KimKS,BockP,GendelmanHE,FialaM:Amodelformonocytemigrationthroughtheblood-brainbarrierduringHIV-1encephalitis.
JImmunol1997,158:3499-3510.
116.
DohguS,BanksWA:Lipopolysaccharide-enhancedtranscellulartransportofHIV-1acrosstheblood-brainbarrierismediatedbythep38mitogen-activatedproteinkinasepathway.
ExpNeurol2008,210:740-749.
117.
Owe-YoungR,WebsterNL,MukhtarM,PomerantzRJ,SmytheG,WalkerD,ArmatiPJ,CroweSM,BrewBJ:Kynureninepathwaymetabolisminhumanblood-brain-barriercells:implicationsforimmunetoleranceandneurotoxicity.
JNeurochem2008,105:1346-1357.
118.
GuilleminGJ,KerrSJ,SmytheGA,SmithDG,KapoorV,ArmatiPJ,CroitoruJ,BrewBJ:Kynureninepathwaymetabolisminhumanastrocytes:aparadoxforneuronalprotection.
JNeurochem2001,78:842-853.
119.
GuilleminGJ,KerrSJ,BrewBJ:InvolvementofquinolinicacidinAIDSdementiacomplex.
NeurotoxRes2005,7:103-123.
120.
CarlinJM,BordenEC,SondelPM,ByrneGI:Interferon-inducedindoleamine2,3-dioxygenaseactivityinhumanmononuclearphagocytes.
JLeukocBiol1989,45:29-34.
121.
HurwitzAA,BermanJW,LymanWD:Theroleoftheblood-brainbarrierinHIVinfectionofthecentralnervoussystem.
AdvNeuroimmunol1994,4:249-256.
122.
SassevilleVG,NewmanW,BrodieSJ,HesterbergP,PauleyD,RinglerDJ:Monocyteadhesiontoendotheliuminsimianimmunodeficiencyvirus-inducedAIDSencephalitisismediatedbyvascularcelladhesionmolecule-1/alpha4beta1integrininteractions.
AmJPathol1994,144:27-40.
123.
RamirezSH,HeilmanD,MorseyB,PotulaR,HaorahJ,PersidskyY:Activationofperoxisomeproliferator-activatedreceptorgamma(PPARgamma)suppressesRhoGTPasesinhumanbrainmicrovascularendothelialcellsandinhibitsadhesionandtransendothelialmigrationofHIV-1infectedmonocytes.
JImmunol2008,180:1854-1865.
124.
IveyNS,RennerNA,Moroney-RasmussenT,MohanM,RedmannRK,DidierPJ,AlvarezX,LacknerAA,MacleanAG:AssociationofFAKactivationwithlentivirus-induceddisruptionofblood-brainbarriertightjunction-associatedZO-1proteinorganization.
JNeurovirol2009:1-12.
125.
NakamutaS,EndoH,HigashiY,KousakaA,YamadaH,YanoM,KidoH:Humanimmunodeficiencyvirustype1gp120-mediateddisruptionoftightjunctionproteinsbyinductionofproteasome-mediateddegradationofzonulaoccludens-1and-2inhumanbrainmicrovascularendothelialcells.
JNeurovirol2008,14:186-195.
126.
ZhongY,SmartEJ,WekslerB,CouraudPO,HennigB,ToborekM:Caveolin-1regulateshumanimmunodeficiencyvirus-1Tat-inducedalterationsoftightjunctionproteinexpressionviamodulationoftheRassignaling.
JNeurosci2008,28:7788-7796.
127.
BermanJW,CarsonMJ,ChangL,CoxBM,FoxHS,GonzalezRG,HansonGR,HauserKF,HoWZ,HongJS,MajorEO,MaragosWF,MasliahE,McArthurJC,MillerDB,NathA,O'CallaghanJP,PersidskyY,PowerC,RogersTJ,RoyalW:NeuroAIDS,drugabuse,andinflammation:buildingcollaborativeresearchactivities.
JNeuroimmunePharmacol2006,1:351-399.
128.
BouwmanFH,SkolaskyRL,HesD,SelnesOA,GlassJD,Nance-SprosonTE,RoyalW,DalPanGJ,McArthurJC:VariableprogressionofHIV-associateddementia.
Neurology1998,50:1814-1820.
129.
KapadiaF,VlahovD,DonahoeRM,FriedlandG:TheroleofsubstanceabuseinHIVdiseaseprogression:reconcilingdifferencesfromlaboratoryandepidemiologicinvestigations.
ClinInfectDis2005,41:1027-1034.
130.
KopniskyKL,BaoJ,LinYW:NeurobiologyofHIV,psychiatricandsubstanceabusecomorbidityresearch:workshopreport.
BrainBehavImmun2007,21:428-441.
131.
MahajanSD,AalinkeelR,SykesDE,ReynoldsJL,BindukumarB,FernandezSF,ChawdaR,ShanahanTC,SchwartzSA:TightjunctionregulationbymorphineandHIV-1tatmodulatesblood-brainbarrierpermeability.
JClinImmunol2008,28:528-541.
132.
MahajanSD,AalinkeelR,SykesDE,ReynoldsJL,BindukumarB,AdalA,QiM,TohJ,XuG,PrasadPN,SchwartzSA:Methamphetaminealtersbloodbrainbarrierpermeabilityviathemodulationoftightjunctionexpression:ImplicationforHIV-1neuropathogenesisinthecontextofdrugabuse.
BrainRes2008,1203:133-148.
133.
DhillonNK,PengF,BokhariS,CallenS,ShinSH,ZhuX,KimKJ,BuchSJ:Cocaine-mediatedalterationintightjunctionproteinexpressionandmodulationofCCL2/CCR2axisacrosstheblood-brainbarrier:implicationsforHIV-dementia.
JNeuroimmunePharmacol2008,3:52-56.
134.
FialaM,GanXH,ZhangL,HouseSD,NewtonT,GravesMC,ShapshakP,StinsM,KimKS,WitteM,ChangSL:Cocaineenhancesmonocytemigrationacrosstheblood-brainbarrier.
Cocaine'sconnectiontoAIDSdementiaandvasculitisAdvExpMedBiol1998,437:199-205.
135.
LuTS,AvrahamHK,SengS,TachadoSD,KozielH,MakriyannisA,AvrahamS:CannabinoidsinhibitHIV-1Gp120-mediatedinsultsinbrainmicrovascularendothelialcells.
JImmunol2008,181:6406-6416.
136.
ShiuC,BarbierE,DiCelloF,ChoiHJ,StinsM:HIV-1gp120aswellasalcoholaffectblood-brainbarrierpermeabilityandstressfiberformation:involvementofreactiveoxygenspecies.
AlcoholClinExpRes2007,31:130-137.
137.
NarayanO,WolinskyJS,ClementsJE,StrandbergJD,GriffinDE,CorkLC:Slowvirusreplication:theroleofmacrophagesinthepersistenceandexpressionofvisnavirusesofsheepandgoats.
JGenVirol1982,59:345-356.
GrasandKaulRetrovirology2010,7:30http://www.
retrovirology.
com/content/7/1/30Page11of11138.
PelusoR,HaaseA,StowringL,EdwardsM,VenturaP:ATrojanHorsemechanismforthespreadofvisnavirusinmonocytes.
Virology1985,147:231-236.
139.
SpudichSS,NilssonAC,LolloND,LieglerTJ,PetropoulosCJ,DeeksSG,PaxinosEE,PriceRW:CerebrospinalfluidHIVinfectionandpleocytosis:relationtosystemicinfectionandantiretroviraltreatment.
BMCInfectDis2005,5:98.
140.
SinclairE,RonquilloR,LolloN,DeeksSG,HuntP,YiannoutsosCT,SpudichS,PriceRW:AntiretroviraltreatmenteffectonimmuneactivationreducescerebrospinalfluidHIV-1infection.
JAcquirImmuneDeficSyndr2008,47:544-552.
doi:10.
1186/1742-4690-7-30Citethisarticleas:GrasandKaul,Molecularmechanismsofneuroinvasionbymonocytes-macrophagesinHIV-1infectionRetrovirology2010,7:30