2024
HIV-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
2022
HIV 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 activationSingle-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
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 HIVFilgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation
Yeh YJ, Jenike KM, Calvi RM, Chiarella J, Hoh R, Deeks SG, Ho YC. Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation. Journal Of Clinical Investigation 2020, 130: 4969-4984. PMID: 32573496, PMCID: PMC7456222, DOI: 10.1172/jci137371.Peer-Reviewed Original ResearchConceptsHIV-1 reactivationHIV-1-infected cellsT cell activationImmune activationHIV-1-induced immune activationCell activationHIV-1 RNA transcriptionHIV-1-infected individualsDrug screensEffective antiretroviral therapyHIV-1 transcriptionFilgotinib treatmentImmune exhaustionAntiretroviral therapyCell line modelsCancer-related gene expressionHIV-1 splicingViral antigensT cellsDrug treatmentHigh-throughput drug screensJAK inhibitorsFilgotinibDruggable targetsDrug candidatesSingle-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target
Liu R, Yeh YJ, Varabyou A, Collora JA, Sherrill-Mix S, Talbot CC, Mehta S, Albrecht K, Hao H, Zhang H, Pollack RA, Beg SA, Calvi RM, Hu J, Durand CM, Ambinder RF, Hoh R, Deeks SG, Chiarella J, Spudich S, Douek DC, Bushman FD, Pertea M, Ho YC. Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target. Science Translational Medicine 2020, 12 PMID: 32404504, PMCID: PMC7453882, DOI: 10.1126/scitranslmed.aaz0802.Peer-Reviewed Original ResearchConceptsHost gene transcriptionGene transcriptionLong terminal repeatHIV-1 reactivationCellular factorsIntegration sitesNonsense-mediated RNA decaySingle-cell transcriptional landscapePotential therapeutic targetSingle-cell transcriptome analysisHIV-1-host interactionsHIV-1HIV-1 promoterTherapeutic targetHIV-1 5' long terminal repeatRNA decayTranscriptional landscapeHIV-1-infected individualsHIV-1-infected cellsTranscriptome analysisAberrant transcriptionRNA transcriptionHost RNACellular survivalTranscription pathway
2016
HIV Drug Resistance Mutations (DRMs) Detected by Deep Sequencing in Virologic Failure Subjects on Therapy from Hunan Province, China
Chen X, Zou X, He J, Zheng J, Chiarella J, Kozal MJ. HIV Drug Resistance Mutations (DRMs) Detected by Deep Sequencing in Virologic Failure Subjects on Therapy from Hunan Province, China. PLOS ONE 2016, 11: e0149215. PMID: 26895182, PMCID: PMC4760947, DOI: 10.1371/journal.pone.0149215.Peer-Reviewed Original ResearchConceptsDrug resistance mutationsVirologic failureDetection of DRMsPrevalence of DRMsSanger sequencingHIV drug resistance mutationsResistance mutationsART-experienced patientsART-experienced subjectsTreatment-experienced subjectsMedian viral loadNNRTI resistance mutationsStandard genotypingART adherenceViral loadAE subtypeMutation prevalenceDeep sequencingFailure subjectsExperienced subjectsResistant variantsOnly variablePatientsPrevalenceSubtypes
2014
Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects
Gupta S, Lataillade M, Kyriakides TC, Chiarella J, St. John EP, Webb S, Moreno EA, Simen BB, Kozal MJ. Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects. Viruses 2014, 6: 3428-3437. PMID: 25256391, PMCID: PMC4189030, DOI: 10.3390/v6093428.Peer-Reviewed Original ResearchConceptsNNRTI resistance mutationsMajor NNRTI-resistance mutationsResistance mutationsAntiretroviral-naïve subjectsARV-naïve HIVMajor NNRTI mutationsNNRTI-resistant variantsTreatment-naïve HIVHIV-1 variantsNon-nucleoside reverseMutational loadNaïve HIVNNRTI mutationsNNRTI resistanceVariant frequencyTrue burdenTherapeutic failureTreatment outcomesTreatment responseAa positionsHIVViral variantsFurther evaluationResistant variantsDeep sequencingPrevalence of WHO Transmitted Drug Resistance Mutations by Deep Sequencing in Antiretroviral-Naïve Subjects in Hunan Province, China
Xiaobai Z, Xi C, Tian H, Williams AB, Wang H, He J, Zhen J, Chiarella J, Blake LA, Turenchalk G, Kozal MJ. Prevalence of WHO Transmitted Drug Resistance Mutations by Deep Sequencing in Antiretroviral-Naïve Subjects in Hunan Province, China. PLOS ONE 2014, 9: e98740. PMID: 24896087, PMCID: PMC4045886, DOI: 10.1371/journal.pone.0098740.Peer-Reviewed Original ResearchConceptsART-naïve subjectsFirst-line antiretroviral therapyLine Antiretroviral TherapyPI TDRsDrug resistance mutationsNNRTI TDRAntiretroviral therapyPI mutationsPI/r useTransmitted Drug Resistance MutationsResistance mutationsAntiretroviral-naïve subjectsAdvanced chronic diseaseHigh-level resistanceAdvanced diseaseNNRTI mutationsNevirapine resistanceNRTI resistanceHIV variantsTime of testingChronic diseasesAE subtypeTreatment responseSubtype AER use
2012
Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing
Lataillade M, Chiarella J, Yang R, DeGrosky M, Uy J, Seekins D, Simen B, St. John E, Moreno E, Kozal M. Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing. PLOS ONE 2012, 7: e30118. PMID: 22355307, PMCID: PMC3280244, DOI: 10.1371/journal.pone.0030118.Peer-Reviewed Original ResearchConceptsPI/rDrug-resistant mutationsVirologic failureUltra-deep sequencingR regimenLow-level resistant variantsMajor PI resistance mutationsPI/r regimenResistant variantsARV-naïve subjectsPI-resistant variantsHIV-positive patientsAtazanavir/ritonavirLopinavir/ritonavirM184V/ILow-level variantsPI resistance mutationsMinority of casesTenofovir/RegimenStanford HIVdbResistance mutationsPhenotypic resistanceResistant mutationsStandard genotyping
2011
Prevalence of Low-Level HIV-1 Variants with Reverse Transcriptase Mutation K65R and the Effect of Antiretroviral Drug Exposure on Variant Levels
Kozal MJ, Chiarella J, St John EP, Moreno EA, Simen BB, Arnold TE, Lataillade M. Prevalence of Low-Level HIV-1 Variants with Reverse Transcriptase Mutation K65R and the Effect of Antiretroviral Drug Exposure on Variant Levels. Antiviral Therapy 2011, 16: 925-929. PMID: 21900725, DOI: 10.3851/imp1851.Peer-Reviewed Original ResearchConceptsTreatment-naive individualsDifferent HIV-1 subtypesARV-naive subjectsHIV-1 subtypesAntiretroviral exposureViral loadSubtype CUltra-deep sequencingReverse Transcriptase Mutation K65RRitonavir-boosted protease inhibitorHIV-1 subtype CResistant variantsAntiretroviral drug exposurePlasma viral loadTreatment-naive subjectsLow-level variantsPre-therapy levelsHIV-1 variantsDrug resistance mutationsMutation K65RVirological failureSubtype BDrug exposureMutational loadHigh mutation load
2007
Natural Polymorphism of the HIV-1 Integrase Gene and Mutations associated with Integrase Inhibitor Resistance
Lataillade M, Chiarella J, Kozal MJ. Natural Polymorphism of the HIV-1 Integrase Gene and Mutations associated with Integrase Inhibitor Resistance. Antiviral Therapy 2007, 12: 563-570. PMID: 17668566, DOI: 10.1177/135965350701200411.Peer-Reviewed Original ResearchConceptsHIV-1 clade BHIV-1 integrase geneINI-naive patientsStrand transfer inhibitorsHIV-1 integrationGene polymorphismsINI resistanceExcellent virological responseClinical HIV-1Late-stage clinical developmentLos Alamos databaseIntegrase inhibitor resistanceNatural polymorphismsHigh-level resistanceI203MVirological responseClade BClinical trialsHIV-1Aa positionsE138KLate-stage developmentClinical developmentA128TDrug resistance