2024
Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation
Kincer L, Dravid A, Trunfio M, Calcagno A, Zhou S, Vercesi R, Spudich S, Gisslen M, Price R, Cinque P, Joseph S. Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation. Journal Of Clinical Investigation 2024, 134: e176358. PMID: 39352388, PMCID: PMC11444166, DOI: 10.1172/jci176358.Peer-Reviewed Original ResearchMeSH KeywordsAdultCD4-Positive T-LymphocytesFemaleHIV InfectionsHIV-1HumansInflammationMaleMiddle AgedRNA, ViralVirus ReplicationConceptsHIV-1 RNACD4+ T cellsHIV-1 populationsAntiretroviral therapyHIV-1T cellsCerebrospinal fluidCSF escapeCNS inflammationDetectable HIV-1 RNAImprovement of neurological symptomsAssociated with viral suppressionUntreated chronic infectionDrug-resistant virusesProgressive neurological deficitsCNS T cellsART regimenViral suppressionChronic infectionNeurological deficitsNeurological symptomsInflammatory biomarkersClinical consequencesVirus expressionPrimary infection
2023
CD4dimCD8bright T cells are inversely associated with neuro-inflammatory markers among people with HIV
Albalawi Y, Shull T, Virdi A, Subra C, Mitchell J, Slike B, Jian N, Krebs S, Sacdalan C, Ratnaratorn N, Hsu D, Phanuphak N, Spudich S, Trautmann L, Al-Harthi L. CD4dimCD8bright T cells are inversely associated with neuro-inflammatory markers among people with HIV. AIDS 2023, 38: 1-7. PMID: 37792358, PMCID: PMC10715695, DOI: 10.1097/qad.0000000000003743.Peer-Reviewed Original ResearchMeSH KeywordsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCognitionHIV InfectionsHumansNeuroinflammatory DiseasesConceptsCombination antiretroviral therapyT cellsWeeks 0CD4-CD8Cerebrospinal fluidImmune activationSoluble markersSuppressive combination antiretroviral therapyPeripheral blood T cellsNeuro-inflammatory markersSubset of CD8Anti-inflammatory propertiesBlood T cellsConfidence intervalsPlasma of peopleT-cell typeCART initiationCSF neopterinPlasma RANTESAntiretroviral therapyWeek 24IP-10IL-6Lumbar punctureIL-8Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus
Letendre S, Chen H, McKhann A, Roa J, Vecchio A, Daar E, Berzins B, Hunt P, Marra C, Campbell T, Coombs R, Ma Q, Swaminathan S, Macatangay B, Morse G, Miller T, Rusin D, Greninger A, Ha B, Alston-Smith B, Robertson K, Paul R, Spudich S, Team T. Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus. Clinical Infectious Diseases 2023, 77: 866-874. PMID: 37183889, PMCID: PMC10506779, DOI: 10.1093/cid/ciad265.Peer-Reviewed Original ResearchMeSH KeywordsAnti-HIV AgentsAntiretroviral Therapy, Highly ActiveCD4-Positive T-LymphocytesFemaleHIV InfectionsHIV-1HumansMaleMiddle AgedViral LoadConceptsAntiretroviral therapyART intensificationNeurocognitive impairmentWeek 48Z-scoreAntiretroviral therapy intensificationPersistent HIV replicationPlacebo-controlled trialPlasma HIV RNASuppressive antiretroviral therapyAge 52 yearsBody mass indexHuman immunodeficiency virusCopies/mLTotal Z-scoreBaseline z-scoresCentral nervous systemDual placeboEfavirenz useTherapy intensificationHIV RNAStudy drugAdverse eventsSymptomatic HIVPrimary outcome
2022
Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones
Collora JA, Liu R, Pinto-Santini D, Ravindra N, Ganoza C, Lama JR, Alfaro R, Chiarella J, Spudich S, Mounzer K, Tebas P, Montaner LJ, van Dijk D, Duerr A, Ho YC. Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones. Immunity 2022, 55: 1013-1031.e7. PMID: 35320704, PMCID: PMC9203927, DOI: 10.1016/j.immuni.2022.03.004.Peer-Reviewed Original ResearchConceptsHIV-1 eradicationHIV-1 RNAHIV-1Effector memory Th1 cellsHIV-1-infected individualsHIV-1-infected CD4Clonal expansionCell clonesMemory Th1 cellsCell clonal expansionPersistent antigenAntiretroviral therapyViral suppressionCytotoxic CD4Cytotoxic TTh1 cellsAntigen stimulationClonal expansion dynamicsUninfected individualsSurface protein expressionTNF responseUnstimulated conditionsTCR sequencesProtein expressionCD4
2021
Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection
Sharma V, Creegan M, Tokarev A, Hsu D, Slike BM, Sacdalan C, Chan P, Spudich S, Ananworanich J, Eller MA, Krebs SJ, Vasan S, Bolton DL. Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection. PLOS Pathogens 2021, 17: e1010105. PMID: 34874976, PMCID: PMC8683024, DOI: 10.1371/journal.ppat.1010105.Peer-Reviewed Original ResearchConceptsT-cell infectionCentral nervous systemAcute HIV-1HIV-1 replicationCerebrospinal fluidT cellsHIV-1Peripheral bloodViral reservoirCell infectionBroad immune activationCerebrospinal fluid CD4CNS viral reservoirCSF T cellsHIV-1 cureActive viral transcriptionLong-term inflammationViral RNACSF CD4Early neuroinflammationAntiretroviral therapyHuman cerebrospinal fluidAcute infectionImmune activationCNS compartmentAbrupt and altered cell-type specific DNA methylation profiles in blood during acute HIV infection persists despite prompt initiation of ART
Corley MJ, Sacdalan C, Pang APS, Chomchey N, Ratnaratorn N, Valcour V, Kroon E, Cho KS, Belden AC, Colby D, Robb M, Hsu D, Spudich S, Paul R, Vasan S, Ndhlovu LC, . Abrupt and altered cell-type specific DNA methylation profiles in blood during acute HIV infection persists despite prompt initiation of ART. PLOS Pathogens 2021, 17: e1009785. PMID: 34388205, PMCID: PMC8386872, DOI: 10.1371/journal.ppat.1009785.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntiretroviral Therapy, Highly ActiveCD4-Positive T-LymphocytesCohort StudiesDNA MethylationHIV InfectionsHIV-1HumansMaleMonocytesViral LoadYoung AdultConceptsAntiretroviral therapyT lymphocytesCD4/CD8 ratioHIV infection cohortHost epigenetic landscapeAcute HIV infectionSpecific DNA methylation profileInfection cohortInfection HIVCD4 countCD8 ratioHIV infectionPrompt initiationViral loadHIV medicineViral persistenceEarly initiationT cellsHIV-1Disease pathogenesisClinical phenotypeMonocytesCD4HIVLymphocytesCompartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression
Gisslen M, Keating SM, Spudich S, Arechiga V, Stephenson S, Zetterberg H, Di Germanio C, Blennow K, Fuchs D, Hagberg L, Norris PJ, Peterson J, Shacklett BL, Yiannoutsos CT, Price RW. Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression. PLOS ONE 2021, 16: e0250987. PMID: 33983973, PMCID: PMC8118251, DOI: 10.1371/journal.pone.0250987.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnti-Retroviral AgentsAntiretroviral Therapy, Highly ActiveBiomarkersCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCentral Nervous SystemCross-Sectional StudiesFemaleHIV InfectionsHIV-1HumansInflammationLeukocyte CountMaleMiddle AgedNeurofilament ProteinsRNA, ViralSerum AlbuminSustained Virologic ResponseConceptsHIV-1 infectionHIV-associated dementiaPrimary HIV-1 infectionBlood CD4CSF inflammationViral suppressionInflammatory biomarkersCNS injuryViral controlT lymphocytesCSF white blood cell countUntreated primary HIV-1 infectionBlood HIV-1 RNACentral nervous system inflammationCerebrospinal fluid inflammatory biomarkersCSF neurofilament light chainHIV-1 seronegative controlsHIV-1-infected subjectsHIV-1-uninfected controlsHIV-1 RNA concentrationsUntreated HIV-1 infectionWhite blood cell countBlood-brain barrier permeabilityCentral nervous system injuryCSF inflammatory response
2020
Determinants of suboptimal CD4+ T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV‐1 infection
Handoko R, Colby DJ, Kroon E, Sacdalan C, de Souza M, Pinyakorn S, Prueksakaew P, Munkong C, Ubolyam S, Akapirat S, Chiarella J, Krebs S, Sereti I, Valcour V, Paul R, Michael NL, Phanuphak N, Ananworanich J, Spudich S, Team T. Determinants of suboptimal CD4+ T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV‐1 infection. Journal Of The International AIDS Society 2020, 23: e25585. PMID: 32949118, PMCID: PMC7507109, DOI: 10.1002/jia2.25585.Peer-Reviewed Original ResearchConceptsAcute HIV infectionCD4/CD8 ratioSuboptimal CD4 recoveryAntiretroviral therapyCD4 countImmune recoveryCD4 recoveryCD8 ratioStudy visitAcute HIV-1 infectionPre-ART CD4 countLower CD8 countsPlasma viral suppressionSuboptimal immune recoveryAntiretroviral therapy initiationT-cell countsT-cell recoveryHIV-1 infectionCopies/mLLower IL-6Cells/ART initiationCD4 rateCD8 countsChronic HIVSelective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy
Gandhi R, Cyktor J, Bosch R, Mar H, Laird G, Martin A, Collier A, Riddler S, Macatangay B, Rinaldo C, Eron J, Siliciano J, McMahon D, Mellors J, Hogg E, LeBlanc R, Scello C, Palm D, Gandhi M, Fletcher C, Podany A, Aweeka F, Halvas L, Dragavon J, Joseph J, Lagattuta R, Lin L, Pederson S, Robertson K, Rubin L, Smith D, Spudich S, Tsibris A. Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy. The Journal Of Infectious Diseases 2020, 223: 225-233. PMID: 32823274, PMCID: PMC7857155, DOI: 10.1093/infdis/jiaa532.Peer-Reviewed Original ResearchConceptsTotal HIV-1 DNAResidual plasma viremiaAntiretroviral therapyHIV-1 DNAProvirus levelsPlasma viremiaLong-term antiretroviral therapyDefective HIV-1 provirusesHIV-1 proviral DNAReplication-competent reservoirSuppressive antiretroviral therapyMarkers of inflammationReplication-competent provirusesHIV-1 provirusART initiationImmune activationHIV-1Proviral DNATime pointsInfected cellsViremiaDefective provirusesInflammationTherapyProvirus
2019
Potential for early antiretroviral therapy to reduce central nervous system HIV-1 persistence.
Spudich S, Peterson J, Fuchs D, Price RW, Gisslen M. Potential for early antiretroviral therapy to reduce central nervous system HIV-1 persistence. AIDS 2019, 33 Suppl 2: s135-s144. PMID: 31789814, DOI: 10.1097/qad.0000000000002326.Peer-Reviewed Original ResearchConceptsHIV-1 infectionCentral nervous systemEarly antiretroviral therapyAntiretroviral therapyHIV-1 persistenceEarly treatmentInitiation of ARTCentral nervous inflammationEarly-treatment cohortHIV-1 exposureHIV-1 reservoirCourse of infectionClinical neurological diseaseCNS infectionHIV reservoirTreatment cohortsImmune activationCNS compartmentViral controlHIV-1Cerebrospinal fluidClinical reportsNervous systemEarly infectionNeurological diseases
2018
Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques
Hsu DC, Sunyakumthorn P, Wegner M, Schuetz A, Silsorn D, Estes JD, Deleage C, Tomusange K, Lakhashe SK, Ruprecht RM, Lombardini E, Im-Erbsin R, Kuncharin Y, Phuang-Ngern Y, Inthawong D, Chuenarom W, Burke R, Robb ML, Ndhlovu LC, Ananworanich J, Valcour V, O'Connell RJ, Spudich S, Michael NL, Vasan S. Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques. Journal Of Virology 2018, 92: 10.1128/jvi.00222-18. PMID: 29563297, PMCID: PMC5952152, DOI: 10.1128/jvi.00222-18.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, Differentiation, MyelomonocyticBrainCD4 Lymphocyte CountCD4-Positive T-LymphocytesCells, CulturedDisease Models, AnimalHIV-1HumansMacaca mulattaMacrophagesMeningesMicrogliaMonocytesParenchymal TissueReceptors, Cell SurfaceRNA, ViralSimian Acquired Immunodeficiency SyndromeSimian immunodeficiency virusViral LoadConceptsSimian-human immunodeficiency virusSimian immunodeficiency virusCD68/CD163Immunodeficiency virus infectionCentral nervous systemBrain parenchymaHIV envelopeImmunodeficiency virusVirus infectionEarly human immunodeficiency virus (HIV) infectionSimian-human immunodeficiency virus (SHIV) infectionCentral nervous system inflammationHuman immunodeficiency virus (HIV) infectionCentral nervous system involvementPathogenic simian immunodeficiency virusRhesus macaquesT-cell-mediated processEarly clinical courseSHIV-infected animalsNervous system inflammationT-cell countsCell-mediated inflammationNervous system involvementEnd-stage diseaseHIV cure strategies
2016
HIV-Associated Neurologic Disorders and Central Nervous System Opportunistic Infections in HIV
Le LT, Spudich SS. HIV-Associated Neurologic Disorders and Central Nervous System Opportunistic Infections in HIV. Seminars In Neurology 2016, 36: 373-381. PMID: 27643907, DOI: 10.1055/s-0036-1585454.Peer-Reviewed Original ResearchMeSH KeywordsAIDS-Related Opportunistic InfectionsCD4-Positive T-LymphocytesHIV InfectionsHumansNervous System DiseasesOpportunistic InfectionsConceptsCombination antiretroviral therapyAsymptomatic neurocognitive impairmentPlasma viral loadViral loadMild neurocognitive disorderCerebral toxoplasmosisCryptococcal meningitisOpportunistic infectionsNeurocognitive disordersCentral nervous system opportunistic infectionsCNS immune reconstitution inflammatory syndromeDetectable plasma viral loadImmune reconstitution inflammatory syndromeCentral nervous system symptomsClassic opportunistic infectionsCSF viral loadProgressive neurologic symptomsReconstitution inflammatory syndromeT-cell countsProgressive multifocal leukoencephalopathyNervous system symptomsPresentation of infectionHigher mortality riskHigher CD4Immune recovery
2015
Phenotypic Correlates of HIV-1 Macrophage Tropism
Arrildt KT, LaBranche CC, Joseph SB, Dukhovlinova EN, Graham WD, Ping LH, Schnell G, Sturdevant CB, Kincer LP, Mallewa M, Heyderman RS, Van Rie A, Cohen MS, Spudich S, Price RW, Montefiori DC, Swanstrom R. Phenotypic Correlates of HIV-1 Macrophage Tropism. Journal Of Virology 2015, 89: 11294-11311. PMID: 26339058, PMCID: PMC4645658, DOI: 10.1128/jvi.00946-15.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, NeutralizingAntibodies, ViralCD4 AntigensCD4-Positive T-LymphocytesCell Line, TumorHEK293 CellsHIV Envelope Protein gp120HIV Envelope Protein gp160HIV Envelope Protein gp41HIV InfectionsHIV-1HumansMacrophagesReceptors, CCR5Recombinant ProteinsViral TropismVirus InternalizationConceptsT cell-tropic virusesT-tropic virusesMonocyte-derived macrophagesM-tropic virusesMacrophage-tropic virusesV1/V2 regionSoluble CD4Central nervous systemHIV-1Chronic infectionT cellsMacrophage-tropic HIV-1 variantsNervous systemM-tropic HIV-1HIV-1 env geneEnv proteinV2 regionT-cell tropicHIV-1 variantsCD4-bound conformationMacrophage-tropicMacrophage tropismM-tropicSurface CD4CD4Cerebral white matter integrity during primary HIV infection
Wright PW, Vaida FF, Fernández R, Rutlin J, Price RW, Lee E, Peterson J, Fuchs D, Shimony JS, Robertson KR, Walter R, Meyerhoff DJ, Spudich S, Ances BM. Cerebral white matter integrity during primary HIV infection. AIDS 2015, 29: 433-442. PMID: 25513818, PMCID: PMC4916955, DOI: 10.1097/qad.0000000000000560.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnti-HIV AgentsBiomarkersBlood-Brain BarrierCD4 Lymphocyte CountCD4-Positive T-LymphocytesCentral Nervous SystemCorpus CallosumCross-Sectional StudiesDiffusion Tensor ImagingHIV InfectionsHIV-1HumansInflammationMaleNeuropsychological TestsProspective StudiesRNA, ViralViral LoadWhite MatterConceptsPrimary HIV infectionLog10 copies/Diffusion tensor imagingBlood-brain barrierHIV infectionWhite matter integrityCopies/Cerebrospinal fluidHIV-1 RNA viral loadMedian CD4 cell countCross-sectional neuroimaging studiesDTI metricsChronic HIV infectionHIV-uninfected (HIV−) participantsDTI measuresCD4 cell countRNA viral loadWhole-brain voxelwise analysisEarly HIV infectionWhite matter involvementBiomarkers of infectionDuration of infectionCentral nervous systemWhite matter microstructural integrityCerebral white matter integrity
2013
Single-copy assay quantification of HIV-1 RNA in paired cerebrospinal fluid and plasma samples from elite controllers
Dahl V, Peterson J, Spudich S, Lee E, Shacklett BL, Price RW, Palmer S. Single-copy assay quantification of HIV-1 RNA in paired cerebrospinal fluid and plasma samples from elite controllers. AIDS 2013, 27: 1145-1149. PMID: 23211774, PMCID: PMC4004626, DOI: 10.1097/qad.0b013e32835cf235.Peer-Reviewed Original ResearchConceptsHIV-1 RNACentral nervous systemHIV-1 RNA quantificationElite controllersCerebrospinal fluidPlasma samplesCSF samplesHIV-1 RNA concentrationsHIV-1-infected individualsConcurrent plasma samplesSingle-copy assayRNA quantificationAntiretroviral therapyCopies/HIV-1Rare subsetNervous systemRNA concentrationClinical assaysSensitive assayAssaysRNATherapyInfectionBlood
2011
Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy
Dahl V, Lee E, Peterson J, Spudich SS, Leppla I, Sinclair E, Fuchs D, Palmer S, Price RW. Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy. The Journal Of Infectious Diseases 2011, 204: 1936-1945. PMID: 22021620, PMCID: PMC3209817, DOI: 10.1093/infdis/jir667.Peer-Reviewed Original ResearchConceptsHIV-1 RNA levelsHIV-1 RNAImmune activationRaltegravir intensificationRNA levelsPlasma human immunodeficiency virus type 1 (HIV-1) RNACSF HIV-1 RNA levelsMedian HIV-1 RNA levelT-cell surface antigen expressionHuman immunodeficiency virus type 1 (HIV-1) RNAOpen-label pilot studySingle-copy assayHIV RNA levelsCerebrospinal fluid infectionHIV-1 infectionCentral nervous systemBaseline viral suppressionSurface antigen expressionT cell activationCSF neopterinIntrathecal immunoactivationSuppressive therapyAntiretroviral therapyTreatment intensificationViral suppression
2009
Compartmentalized Human Immunodeficiency Virus Type 1 Originates from Long-Lived Cells in Some Subjects with HIV-1–Associated Dementia
Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R. Compartmentalized Human Immunodeficiency Virus Type 1 Originates from Long-Lived Cells in Some Subjects with HIV-1–Associated Dementia. PLOS Pathogens 2009, 5: e1000395. PMID: 19390619, PMCID: PMC2668697, DOI: 10.1371/journal.ppat.1000395.Peer-Reviewed Original ResearchConceptsHIV-1-associated dementiaCentral nervous systemAntiretroviral therapyCerebrospinal fluidNeurological diseasesAsymptomatic subjectsHIV-1-associated neurological diseasePeripheral CD4 cell countViral replicationHuman immunodeficiency virus type 1HIV-1 associated dementiaViral decayImmunodeficiency virus type 1HIV-1 genetic variantsCNS drug penetrationRapid viral decayViral decay kineticsCD4 cell countDrug-resistant virusesHigh viral loadHIV-1 variantsVirus type 1Productive viral replicationHAD subjectsCSF pleocytosis
2008
Failure of atorvastatin to modulate CSF HIV-1 infection
Probasco JC, Spudich SS, Critchfield J, Lee E, Lollo N, Deeks SG, Price RW. Failure of atorvastatin to modulate CSF HIV-1 infection. Neurology 2008, 71: 521-524. PMID: 18695163, PMCID: PMC2676982, DOI: 10.1212/01.wnl.0000325006.84658.e7.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHIV-1 RNA levelsT-cell countsCell countIntrathecal immunoactivationNeopterin concentrationsBlood lipidsBlood HIV-1 RNA levelCSF HIV-1 RNA levelsCSF white blood cell countCNS HIV-1 infectionSystemic HIV-1 infectionSingle-arm pilot studyWhite blood cell countPilot studyAntiretroviral-naïve subjectsCells/mulRNA levelsUntreated systemic infectionT-lymphocyte countsSmall uncontrolled studiesEffect of atorvastatinHMG-CoA reductase inhibitorsWeeks of treatmentHIV-1 RNA