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 ResearchConceptsHIV-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 infectionChanges in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection
Hu Z, Cinque P, Dravid A, Hagberg L, Yilmaz A, Zetterberg H, Fuchs D, Gostner J, Blennow K, Spudich S, Kincer L, Zhou S, Joseph S, Swanstrom R, Price R, Gisslén M. Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection. PLOS Pathogens 2024, 20: e1012470. PMID: 39316609, PMCID: PMC11469498, DOI: 10.1371/journal.ppat.1012470.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHIV-associated dementiaCerebrospinal fluidCerebrospinal fluid proteinCerebrospinal fluid HIV-1 RNAImpact of HIV-1 infectionTreating chronic HIV-1 infectionChronic HIV-1 infectionHIV-1 RNAHIV-1 progressionTreat chronic infectionsInflammatory cell lineagesNeurofilament light chain proteinCSF escapeChronic infectionHIV-1Light chain proteinProtein changesClinical centersCNS injuryCSF proteinClinical informationCell lineagesInfectionCerebrospinal fluid proteomeTranscobalamin receptor antibodies in autoimmune vitamin B12 central deficiency
Pluvinage J, Ngo T, Fouassier C, McDonagh M, Holmes B, Bartley C, Kondapavulur S, Hurabielle C, Bodansky A, Pai V, Hinman S, Aslanpour A, Alvarenga B, Zorn K, Zamecnik C, McCann A, Asencor A, Huynh T, Browne W, Tubati A, Haney M, Douglas V, Louine M, Cree B, Hauser S, Seeley W, Baranzini S, Wells J, Spudich S, Farhadian S, Ramachandran P, Gillum L, Hales C, Zikherman J, Anderson M, Yazdany J, Smith B, Nath A, Suh G, Flanagan E, Green A, Green R, Gelfand J, DeRisi J, Pleasure S, Wilson M. Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Science Translational Medicine 2024, 16: eadl3758. PMID: 38924428, PMCID: PMC11520464, DOI: 10.1126/scitranslmed.adl3758.Peer-Reviewed Original ResearchConceptsBlood-brain barrierCerebrospinal fluidNeurological deficitsAutoimmune neurological conditionsCohort of patientsCellular uptake of cobalaminVitamin B12B12 transportCerebrospinal fluid samplesMeasurement of vitamin B12Low-density lipoprotein receptorProgrammable phage displayImmunosuppressive treatmentIn vitro modelNeuropsychiatric lupusImmunomodulatory treatmentReceptor antibodiesClinical improvementUptake of cobalaminB12 deficiencyUnknown etiologyHematopoietic cellsTranscobalamin receptorCentral deficiencyB12 supplementationPrevalence of detectable HIV-DNA and HIV-RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy
Wagner T, Tierney C, Huang S, Nichols S, Malee K, Montañez N, Coletti A, Spiegel H, Krotje C, Bone F, Wilkins M, Abuogi L, Purswani M, Bearden A, Wiznia A, Agwu A, Chadwick E, Richman D, Gandhi M, Mehta P, Macatangay B, Spector S, Spudich S, Persaud D, Chahroudi A, Team F. Prevalence of detectable HIV-DNA and HIV-RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy. AIDS 2024, 38: 1494-1504. PMID: 38814693, PMCID: PMC11239098, DOI: 10.1097/qad.0000000000003937.Peer-Reviewed Original ResearchCell-free HIV RNAAntiretroviral therapyHIV DNACentral nervous systemDetect HIV DNACerebrospinal fluidHIV RNAPerinatal HIVLong-term virologic suppressionFluid cognition composite scoresSuppressive antiretroviral therapyCerebrospinal fluid cellsHair antiretroviral concentrationsHIV DNA detectionQuantify HIVVirologic suppressionAntiretroviral concentrationsCD4 countCerebrospinal fluid collectionHIV infectionHIV GagPol DNANeurocognitive impairmentCognitive impairmentHIVHIV-1–infected T cell clones are shared across cerebrospinal fluid and blood during ART
Wang M, Yoon J, Reisert H, Das B, Orlinick B, Chiarella J, Halvas E, Mellors J, Pang A, Barakat L, Fikrig M, Cyktor J, Kluger Y, Spudich S, Corley M, Farhadian S. HIV-1–infected T cell clones are shared across cerebrospinal fluid and blood during ART. JCI Insight 2024, 9: e176208. PMID: 38587074, PMCID: PMC11128194, DOI: 10.1172/jci.insight.176208.Peer-Reviewed Original ResearchConceptsT cell clonesT cell receptorCerebrospinal fluidT cellsHIV-1Infected T-cell clonesCentral memory T cellsCD4 T-cell clonesDetectable HIV RNAMemory T cellsHIV-1 RNAInfected T cellsCNS reservoirsHIV persistenceHIV reservoirHIV RNAHIV cureReservoir cellsPWHTissue compartmentsBloodCNSUninfected controlsCD4Infected cells
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 ResearchConceptsCombination 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-8Rebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus
Kincer L, Joseph S, Gilleece M, Hauser B, Sizemore S, Zhou S, Di Germanio C, Zetterberg H, Fuchs D, Deeks S, Spudich S, Gisslen M, Price R, Swanstrom R. Rebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus. Nature Microbiology 2023, 8: 260-271. PMID: 36717718, PMCID: PMC10201410, DOI: 10.1038/s41564-022-01306-6.Peer-Reviewed Original ResearchConceptsCentral nervous systemT cell-tropic virusesInfected T cellsCerebrospinal fluidAntiretroviral therapyHIV-1Rebound virusViral loadT cellsMacrophage-tropic HIV-1CSF viral loadSuppressive antiretroviral therapyHIV-1 reservoirMacrophage-tropic virusesHigh viral loadWhite blood cellsTherapy interruptionLatent reservoirLymphoid systemNervous systemSystemic infectionVirus replicationBlood cellsTransient influxVirusHIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells
Kincer L, Schnell G, Swanstrom R, Miller M, Spudich S, Eron J, Price R, Joseph S. HIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells. Pathogens And Immunity 2023, 7: 131-142. PMID: 36865569, PMCID: PMC9973728, DOI: 10.20411/pai.v7i2.524.Peer-Reviewed Original ResearchBlood-cerebrospinal fluid barrierBlood-brain barrierCentral nervous systemHIV-1Cerebrospinal fluidInfected cellsCSF samplesNervous systemCo-infected participantsHCV viral loadHIV-1 replicationCross-sectional studyMigration of HIVHIV-1 particlesHIV-1 populationsBlood plasmaHCV concentrationAntiviral regimensViral loadHCV entryInflammatory responseFluid barrierHCVVirus entryNormal surveillance
2022
OP 4.5 – 00101 Comparative single-cell transcriptome and TCR profiling of HIV infected cells in the blood and cerebrospinal fluid of PLWH before and after ART
Wang M, Corley M, Yoon J, Chiarella J, Cyktor J, Spudich S, Kluger Y, Farhadian S. OP 4.5 – 00101 Comparative single-cell transcriptome and TCR profiling of HIV infected cells in the blood and cerebrospinal fluid of PLWH before and after ART. Journal Of Virus Eradication 2022, 8: 100205. DOI: 10.1016/j.jve.2022.100205.Peer-Reviewed Original ResearchHIV viral transcription and immune perturbations in the CNS of people with HIV despite ART
Farhadian SF, Lindenbaum O, Zhao J, Corley MJ, Im Y, Walsh H, Vecchio A, Garcia-Milian R, Chiarella J, Chintanaphol M, Calvi R, Wang G, Ndhlovu LC, Yoon J, Trotta D, Ma S, Kluger Y, Spudich S. HIV viral transcription and immune perturbations in the CNS of people with HIV despite ART. JCI Insight 2022, 7: e160267. PMID: 35801589, PMCID: PMC9310520, DOI: 10.1172/jci.insight.160267.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidHIV infectionHIV-1-infected cellsCNS viral persistenceCentral memory CD4T-cell abnormalitiesHIV-1 RNAMicroglia-like cellsT cell activationSystemic viral suppressionAbnormal CD8HIV neuropathogenesisViral suppressionMemory CD4CNS reservoirsImmune perturbationsExperience elevated ratesNeuroimmune effectsPeripheral bloodNeurological impairmentViral persistenceT cellsCell abnormalitiesUninfected controlsCell activation
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 compartmentVZV myelitis with secondary HIV CSF escape
Weiss JJ, Spudich S, Barakat L. VZV myelitis with secondary HIV CSF escape. BMJ Case Reports 2021, 14: e241738. PMID: 34187795, PMCID: PMC8245447, DOI: 10.1136/bcr-2021-241738.Peer-Reviewed Case Reports and Technical NotesConceptsVaricella-zoster virusCSF escapeVZV myelitisSkin lesionsCerebrospinal fluidCSF HIV viral loadRight upper extremity weaknessCentral nervous system infectionSubsequent oral therapyUpper extremity weaknessHIV viral loadNervous system infectionVesicular skin lesionsCopies/mLDirect fluorescent antibody testingFluorescent antibody testingIntravenous acyclovirVZV PCRExtremity weaknessOral therapyRare complicationSystem infectionAtypical presentationImmunosuppressed patientsVZV infectionDivergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms
Song E, Bartley CM, Chow RD, Ngo TT, Jiang R, Zamecnik CR, Dandekar R, Loudermilk RP, Dai Y, Liu F, Sunshine S, Liu J, Wu W, Hawes IA, Alvarenga BD, Huynh T, McAlpine L, Rahman NT, Geng B, Chiarella J, Goldman-Israelow B, Vogels CBF, Grubaugh ND, Casanovas-Massana A, Phinney BS, Salemi M, Alexander JR, Gallego JA, Lencz T, Walsh H, Wapniarski AE, Mohanty S, Lucas C, Klein J, Mao T, Oh J, Ring A, Spudich S, Ko AI, Kleinstein SH, Pak J, DeRisi JL, Iwasaki A, Pleasure SJ, Wilson MR, Farhadian SF. Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms. Cell Reports Medicine 2021, 2: 100288. PMID: 33969321, PMCID: PMC8091032, DOI: 10.1016/j.xcrm.2021.100288.Peer-Reviewed Original ResearchNeurological symptomsImmune responseCerebrospinal fluidAnti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodiesCOVID-19Self-reactive immune responsesSARS-CoV-2 antibodiesCompartmentalized immune responseCSF immunoglobulin GRole of autoimmunityCOVID-19 patientsB cell responsesCoronavirus disease 2019Immune surveyNeurologic sequelaePulmonary infectionBrain infectionSerum antibodiesDisease 2019Monoclonal antibody targetsAnimal modelsTarget epitopesCell activationCell responsesSingle-cell RNA sequencing
2019
Markers of CNS Injury in Adults Living With HIV With CSF HIV Not Detected vs Detected <20 Copies/mL
Farhadian SF, Mistry H, Kirchwey T, Chiarella J, Calvi R, Chintanaphol M, Patel P, Landry ML, Robertson K, Spudich SS. Markers of CNS Injury in Adults Living With HIV With CSF HIV Not Detected vs Detected <20 Copies/mL. Open Forum Infectious Diseases 2019, 6: ofz528. PMID: 31893212, PMCID: PMC6934883, DOI: 10.1093/ofid/ofz528.Peer-Reviewed Original ResearchAntiretroviral therapyHIV RNACerebrospinal fluidBlood-brain barrier integrityCentral nervous system pathologyCNS immune activationCSF HIV RNANervous system pathologyCSF HIVCSF RNAImmune activationCNS injuryCopies/Neuropsychological testingSystem pathologyBarrier integrityCNS parametersHIVStandard assayExecutive functionRNAInjuryTherapySignificance of RNAPathologyPotential 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 diseasesDefining cerebrospinal fluid HIV RNA escape: editorial review AIDS.
Winston A, Antinori A, Cinque P, Fox HS, Gisslen M, Henrich TJ, Letendre S, Persaud D, Price RW, Spudich S. Defining cerebrospinal fluid HIV RNA escape: editorial review AIDS. AIDS 2019, 33 Suppl 2: s107-s111. PMID: 31790376, DOI: 10.1097/qad.0000000000002252.Peer-Reviewed Original ResearchDeep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection
Tovanabutra S, Sirijatuphat R, Pham PT, Bonar L, Harbolick EA, Bose M, Song H, Chang D, Oropeza C, O’Sullivan A, Balinang J, Kroon E, Colby DJ, Sacdalan C, Hellmuth J, Chan P, Prueksakaew P, Pinyakorn S, Jagodzinski LL, Sutthichom D, Pattamaswin S, de Souza M, Gramzinski RA, Kim JH, Michael NL, Robb ML, Phanuphak N, Ananworanich J, Valcour V, Kijak GH, Sanders-Buell E, Spudich S, Core T, Team T. Deep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection. Cells 2019, 8: 902. PMID: 31443253, PMCID: PMC6721674, DOI: 10.3390/cells8080902.Peer-Reviewed Original ResearchConceptsAcute HIV-1 infectionCentral nervous systemHIV-1 infectionCerebrospinal fluidCNS compartmentalizationHIV-1HIV-1 compartmentalizationHIV-1 exposureHIV-1 neuropathogenesisHIV-1 reservoirSingle-genome sequencingHIV reservoirFounder virusesRemission strategiesNeurological impairmentNervous systemF infectionsViral replicationInfectionPotential long-term implicationsNext-generation sequencingEnvelope geneTissue compartmentsF variantLong-term implicationsPersistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance
Spudich S, Robertson KR, Bosch RJ, Gandhi RT, Cyktor JC, Mar H, Macatangay BJ, Lalama CM, Rinaldo C, Collier AC, Godfrey C, Eron JJ, McMahon D, Jacobs JL, Koontz D, Hogg E, Vecchio A, Mellors JW. Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance. Journal Of Clinical Investigation 2019, 129: 3339-3346. PMID: 31305262, PMCID: PMC6668666, DOI: 10.1172/jci127413.Peer-Reviewed Original ResearchConceptsLong-term antiretroviral therapyPeripheral blood mononuclear cellsAntiretroviral therapyHIV RNACerebrospinal fluidPoorer neurocognitive performanceInflammatory biomarkersNeurocognitive performanceCell-associated HIV DNACell-free HIV RNAHigher plasma HIV RNAYears of ARTCSF HIV RNACSF inflammatory biomarkersWorse neurocognitive outcomesNadir CD4 countPlasma HIV RNABlood mononuclear cellsQuantitative PCRGlobal deficit scoreHalf of individualsCell-free RNACSF supernatantHIV persistenceCD4 countPredicting Efavirenz Concentrations in the Brain Tissue of HIV‐Infected Individuals and Exploring their Relationship to Neurocognitive Impairment
Srinivas N, Joseph SB, Robertson K, Kincer LP, Menezes P, Adamson L, Schauer AP, Blake KH, White N, Sykes C, Luciw P, Eron JJ, Forrest A, Price R, Spudich S, Swanstrom R, Kashuba A. Predicting Efavirenz Concentrations in the Brain Tissue of HIV‐Infected Individuals and Exploring their Relationship to Neurocognitive Impairment. Clinical And Translational Science 2019, 12: 302-311. PMID: 30675981, PMCID: PMC6510381, DOI: 10.1111/cts.12620.Peer-Reviewed Original ResearchConceptsBrain tissue concentrationsCerebrospinal fluidBrain tissueRhesus macaquesNeurocognitive scoresPK/pharmacodynamic analysesPenetration of antiretroviralsTissue concentrationsExposure-response analysisConcentration-time curveAdult rhesus macaquesCSF AUCEfavirenz concentrationsPlasma AUCPharmacodynamic analysisClinical studiesTissue AUCNeurocognitive impairmentCSF samplesPharmacokinetic dataPK modelingHIVTime pointsAUCNecropsyVery Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma
Hellmuth J, Slike BM, Sacdalan C, Best J, Kroon E, Phanuphak N, Fletcher JLK, Prueksakaew P, Jagodzinski LL, Valcour V, Robb M, Ananworanich J, Allen IE, Krebs SJ, Spudich S. Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma. The Journal Of Infectious Diseases 2019, 220: 1885-1891. PMID: 30668739, PMCID: PMC6833977, DOI: 10.1093/infdis/jiz030.Peer-Reviewed Original ResearchConceptsAcute HIV infectionAntiretroviral therapyART initiationCerebrospinal fluidWeek 96Week 24HIV infectionImmune activationAHI groupHuman immunodeficiency virus (HIV) infectionEarly ART initiationPlasma CCL2 levelsTrajectory of HIVChronic immune activationImmune activation markersSuppressive antiretroviral therapyImmunodeficiency virus infectionInterleukin-6 levelsMarkers of inflammationPlasma neopterin levelsWeeks of treatmentCentral nervous systemART regimenCCL2 levelsNeopterin levels