2024
Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid
Papini C, Ullah I, Ranjan A, Zhang S, Wu Q, Spasov K, Zhang C, Mothes W, Crawford J, Lindenbach B, Uchil P, Kumar P, Jorgensen W, Anderson K. Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2320713121. PMID: 38621119, PMCID: PMC11046628, DOI: 10.1073/pnas.2320713121.Peer-Reviewed Original ResearchConceptsDirect-acting antiviralsSARS-CoV-2Lack of off-target effectsIn vitro pharmacological profileTreatment of patientsDevelopment of severe symptomsPharmacological propertiesDrug-drug interactionsSARS-CoV-2 infectionProof-of-concept studySARS-CoV-2 M<sup>pro</sup>.Combination regimenImmunocompromised patientsLead compoundsSARS-CoV-2 main proteaseOral doseActive drugTreat infectionsPharmacological profileSARS-CoV-2 MPotential preclinical candidateOff-target effectsPatientsComplete recoveryCapsule formulation
2023
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons D, Kumar P, Roan N, Defechereux P, Feschotte C, Lange U, Murthy N, Sameshima P, Verdin E, Ake J, Parsons M, Nath A, Gianella S, Smith D, Kallas E, Villa T, Strange R, Mwesigwa B, O’Brien R, Nixon D, Ndhlovu L, Valente S, Ott M. HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing. Viruses 2023, 15: 2171. PMID: 38005849, PMCID: PMC10674359, DOI: 10.3390/v15112171.Peer-Reviewed Original ResearchExploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells
Behrens R, Rajashekar J, Bruce J, Evans E, Hansen A, Salazar-Quiroz N, Simons L, Ahlquist P, Hultquist J, Kumar P, Sherer N. Exploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells. MBio 2023, 14: e00420-23. PMID: 37676006, PMCID: PMC10653828, DOI: 10.1128/mbio.00420-23.Peer-Reviewed Original ResearchConceptsCyclin T1Species-specific differencesViral gene expressionGene expressionHost proteinsIntron-containing viral RNAsBroad-spectrum resistanceHost cell biologyCRISPR/Cas9 geneLatency reversal agentsIsogenic cell linesHuman T cellsEfficient HIV-1 transcriptionHIV-1 gene expressionCell linesViral RNA transcriptionT cellsSpecies-specific regionsCell-intrinsic defectHIV-1 virion productionHousekeeping proteinsNuclear exportRNA transcriptionCell biologyCas9 gene
2022
HIV-1 Vpu restricts Fc-mediated effector functions in vivo
Prévost J, Anand S, Rajashekar J, Zhu L, Richard J, Goyette G, Medjahed H, Gendron-Lepage G, Chen H, Chen Y, Horwitz J, Grunst M, Zolla-Pazner S, Haynes B, Burton D, Flavell R, Kirchhoff F, Hahn B, Smith A, Pazgier M, Nussenzweig M, Kumar P, Finzi A. HIV-1 Vpu restricts Fc-mediated effector functions in vivo. Cell Reports 2022, 41: 111624. PMID: 36351384, PMCID: PMC9703018, DOI: 10.1016/j.celrep.2022.111624.Peer-Reviewed Original ResearchConceptsAntibody-dependent cellular cytotoxicityEffector functionsFc-mediated effector functionsHIV-1-infected cellsWild-type virusCorrelates of protectionRV144 vaccine trialHIV-1 infectionNon-neutralizing antibodiesFc effector functionsCell surface CD4Viral envelope glycoproteinsViral loadHumanized miceHumoral responseVaccine trialsCellular cytotoxicityHIV-1 VpuVpu expressionEnvelope glycoproteinInfected cellsNnAbsVirusVpuAdministrationA Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection
Beaudoin-Bussières G, Chen Y, Ullah I, Prévost J, Tolbert WD, Symmes K, Ding S, Benlarbi M, Gong SY, Tauzin A, Gasser R, Chatterjee D, Vézina D, Goyette G, Richard J, Zhou F, Stamatatos L, McGuire AT, Charest H, Roger M, Pozharski E, Kumar P, Mothes W, Uchil PD, Pazgier M, Finzi A. A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection. Cell Reports 2022, 38: 110368. PMID: 35123652, PMCID: PMC8786652, DOI: 10.1016/j.celrep.2022.110368.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingAntibodies, ViralAntibody-Dependent Cell CytotoxicityCOVID-19COVID-19 SerotherapyDisease Models, AnimalEpitopesHumansImmunization, PassiveImmunoglobulin Fab FragmentsImmunoglobulin Fc FragmentsMiceProtein BindingProtein ConformationSARS-CoV-2Spike Glycoprotein, Coronavirus
2021
Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy
Ullah I, Prévost J, Ladinsky MS, Stone H, Lu M, Anand SP, Beaudoin-Bussières G, Symmes K, Benlarbi M, Ding S, Gasser R, Fink C, Chen Y, Tauzin A, Goyette G, Bourassa C, Medjahed H, Mack M, Chung K, Wilen CB, Dekaban GA, Dikeakos JD, Bruce EA, Kaufmann DE, Stamatatos L, McGuire AT, Richard J, Pazgier M, Bjorkman PJ, Mothes W, Finzi A, Kumar P, Uchil PD. Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy. Immunity 2021, 54: 2143-2158.e15. PMID: 34453881, PMCID: PMC8372518, DOI: 10.1016/j.immuni.2021.08.015.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent subjectsSARS-CoV-2 infectionBioluminescence imagingK18-hACE2 miceLive bioluminescence imagingNatural killer cellsFc effector functionsSARS-CoV-2Convalescent subjectsKiller cellsPotent NAbsImmune protectionInflammatory responseEffector functionsNasal cavityNaB treatmentOptimal efficacyFc functionDepletion studiesMiceNAbsCOVID-19Direct neutralizationInfectionAntibodiesModulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir
Rajashekar JK, Richard J, Beloor J, Prévost J, Anand SP, Beaudoin-Bussières G, Shan L, Herndler-Brandstetter D, Gendron-Lepage G, Medjahed H, Bourassa C, Gaudette F, Ullah I, Symmes K, Peric A, Lindemuth E, Bibollet-Ruche F, Park J, Chen HC, Kaufmann DE, Hahn BH, Sodroski J, Pazgier M, Flavell RA, Smith AB, Finzi A, Kumar P. Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir. Cell Host & Microbe 2021, 29: 904-916.e6. PMID: 34019804, PMCID: PMC8214472, DOI: 10.1016/j.chom.2021.04.014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingAntibody-Dependent Cell CytotoxicityAntiviral AgentsCD4 AntigensCD4-Positive T-LymphocytesCell LineEnv Gene Products, Human Immunodeficiency VirusEpitopesFemaleGlycoproteinsHEK293 CellsHIV InfectionsHIV-1HumansImmunoglobulin Fc FragmentsKiller Cells, NaturalMaleMiceMice, SCIDModels, AnimalProtein ConformationVirus ReplicationConceptsAntibody-dependent cellular cytotoxicityHIV-1 reservoirFc effector functionsViral reboundHumanized miceHIV-1HIV-1-infected individualsHIV-1-infected cellsAutologous HIV-1Natural killer cellsCD4-mimetic compoundsHIV-1 replicationSmall CD4-mimetic compoundsART interruptionFunctional cureNK cellsKiller cellsCellular cytotoxicityTherapeutic utilityInfected individualsCD4mcVirus reservoirMiceViral envelopeAntibody recognition
2020
Targeted Delivery of Recombinant Heat Shock Protein 27 to Cardiomyocytes Promotes Recovery from Myocardial Infarction
Kim N, Ullah I, Chung K, Lee D, Cha MJ, Ban H, Choi CS, Kim S, Hwang KC, Kumar P, Lee SK. Targeted Delivery of Recombinant Heat Shock Protein 27 to Cardiomyocytes Promotes Recovery from Myocardial Infarction. Molecular Pharmaceutics 2020, 17: 2034-2043. PMID: 32364395, DOI: 10.1021/acs.molpharmaceut.0c00192.Peer-Reviewed Original ResearchConceptsAT1 receptor antibodyIschemic heart diseaseIschemia/reperfusionMyocardial infarctionMI ratsReceptor antibodiesHeart diseaseAngiotensin II type 1 receptorII type 1 receptorType 1 receptorAreas of fibrosisHeat shock protein 27Cause of deathRat MI modelShock protein 27Hypoxia-induced apoptosisIschemic injuryTherapeutic optionsCardiac functionProtective effectPromotes recoveryCardiomyocyte deathNormal responseMI modelSystemic deliverySingle cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures
Zhao Y, Amodio M, Vander Wyk B, Gerritsen B, Kumar MM, van Dijk D, Moon K, Wang X, Malawista A, Richards MM, Cahill ME, Desai A, Sivadasan J, Venkataswamy MM, Ravi V, Fikrig E, Kumar P, Kleinstein SH, Krishnaswamy S, Montgomery RR. Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures. PLOS Neglected Tropical Diseases 2020, 14: e0008112. PMID: 32150565, PMCID: PMC7082063, DOI: 10.1371/journal.pntd.0008112.Peer-Reviewed Original ResearchConceptsZika virusCell subsetsDengue virusConcurrent dengue infectionInnate cell responsesInnate immune signaturesVirus-infected individualsDivergent clinical outcomesMosquito-borne human pathogenIntact immune responsePre-existing infectionInnate cell typesSingle-cell immune profilingPublic health importanceCell typesImmune signaturesVirus patientsWest Nile virusAcute patientsClinical outcomesImmune profilingDengue infectionImmune statusFunctional statusImmune cells
2019
Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice
Ventura JD, Beloor J, Allen E, Zhang T, Haugh KA, Uchil PD, Ochsenbauer C, Kieffer C, Kumar P, Hope TJ, Mothes W. Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice. PLOS Pathogens 2019, 15: e1008161. PMID: 31805155, PMCID: PMC6917343, DOI: 10.1371/journal.ppat.1008161.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHumanized miceCombination antiretroviral therapy regimenViral spreadHIV-1 infection dynamicsNon-invasive bioluminescentAntiretroviral therapy regimenHIV-1 reporterSame lymphoid tissuesInfected cell populationCART withdrawalInfection recrudescenceAntiretroviral therapyTreatment interruptionTherapy regimenLymphoid tissueInfection dynamicsART treatmentBioluminescent imagingInfectionViral infection dynamicsInfected cellsCell populationsMiceBioluminescent signalA Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System.
Ullah I, Chung K, Beloor J, Lee SK, Kumar P. A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System. Journal Of Visualized Experiments 2019 PMID: 31475960, DOI: 10.3791/59201.Peer-Reviewed Original ResearchConceptsCentral nervous systemBlood-brain barrierNervous systemIntranasal drug deliveryBody temperatureMin rest periodMouse body temperatureCNS uptakeReceptor-binding domainRabies virus glycoproteinCNS deliveryAnesthetized miceDominant handNondominant handMiceInhalationDelivery of siRNASiRNA approachDelivery of drugsRest periodHeating padMouse headAdministrationVirus glycoproteinForward positionIntroducing Genes into Cultured Mammalian Cells
Kumar P, Nagarajan A, Uchil PD. Introducing Genes into Cultured Mammalian Cells. Cold Spring Harbor Protocols 2019, 2019: pdb.top095406. PMID: 31285274, DOI: 10.1101/pdb.top095406.Peer-Reviewed Original ResearchDNA Transfection by Electroporation.
Kumar P, Nagarajan A, Uchil PD. DNA Transfection by Electroporation. Cold Spring Harbor Protocols 2019, 2019: pdb.prot095471. PMID: 31262956, DOI: 10.1101/pdb.prot095471.Peer-Reviewed Original ResearchDNA Transfection Mediated by Cationic Lipid Reagents
Kumar P, Nagarajan A, Uchil PD. DNA Transfection Mediated by Cationic Lipid Reagents. Cold Spring Harbor Protocols 2019, 2019: pdb.prot095414. PMID: 30824617, DOI: 10.1101/pdb.prot095414.Peer-Reviewed Original ResearchConceptsCell typesSpecific cell typesCationic lipid reagentsSuspension cell typesDNA transfectionLiposomal transfection reagentTransfection procedureCell linesLipid reagentsFuGENE 6Transfection reagentPresence of serumLipofectamine 2000Number of manipulationsGeneralistsTransfectionAlternative protocolManipulationCellsMost adherentLipofectin
2016
Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary
Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC, Casares S, Garcia JV, Hasenkrug KJ, Kashanchi F, Kitchen SG, Klein F, Kumar P, Luster AD, Poluektova LY, Rao M, Sanders-Beer BE, Shultz LD, Zack JA. Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary. AIDS Research And Human Retroviruses 2016, 32: 109-119. PMID: 26670361, PMCID: PMC4761823, DOI: 10.1089/aid.2015.0258.Peer-Reviewed Original ResearchConceptsHuman leukocyte antigenHumanized mouse modelHuman immunodeficiency virusMouse modelCell engraftmentHuman hematopoietic cell engraftmentNIH/NIAIDHIV immune responsesImmunodeficient mouse strainsHematopoietic cell engraftmentHuman T cellsHIV reservoirXenogeneic graftImmunodeficiency syndromeHumanized miceImmunodeficiency virusLymphoid structuresLeukocyte antigenNew imaging techniquesT cellsImmune responseImmunodeficient miceHost responseHIV researchInfectious diseases
2015
Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection
Sewald X, Ladinsky MS, Uchil PD, Beloor J, Pi R, Herrmann C, Motamedi N, Murooka TT, Brehm MA, Greiner DL, Shultz LD, Mempel TR, Bjorkman PJ, Kumar P, Mothes W. Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. Science 2015, 350: 563-567. PMID: 26429886, PMCID: PMC4651917, DOI: 10.1126/science.aab2749.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virusLymph nodesMurine leukemia virusCD169/SiglecSecondary lymphoid tissuesPermissive lymphocytesDendritic cellsImmunodeficiency virusSynaptic contactsLymphoid tissueRobust infectionVirological synapsesI-type lectinsRetroviral spreadViral spreadUninfected cellsInfectionLeukemia virusVirusMacrophagesCellsRetrovirusesCell-cell contactCD169LymphocytesAdenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice
Liu S, Jackson A, Beloor J, Kumar P, Sutton RE. Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice. Human Gene Therapy 2015, 26: 622-634. PMID: 25953321, PMCID: PMC4575530, DOI: 10.1089/hum.2014.146.Peer-Reviewed Original ResearchConceptsHumanized miceHuman immunodeficiency virus type 1 (HIV-1) acquisitionHuman immunodeficiency virus type 1Immunodeficiency virus type 1Plasma viral loadHigher serum levelsSingle intramuscular injectionBroadly Neutralizing AntibodiesVirus type 1First-generation adenoviral vectorsSerum levelsViral loadNeutralizing antibodiesIntramuscular injectionEffective vaccineT cellsHIV-1Therapeutic approachesHigh doseTherapeutic useType 1Adenoviral vectorAdV vectorsMiceAntibodiesBroad CTL response is required to clear latent HIV-1 due to dominance of escape mutations
Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 2015, 517: 381-385. PMID: 25561180, PMCID: PMC4406054, DOI: 10.1038/nature14053.Peer-Reviewed Original ResearchMeSH KeywordsAcute DiseaseAnimalsAnti-HIV AgentsCD4-Positive T-LymphocytesChronic DiseaseEpitopes, T-LymphocyteFemaleGag Gene Products, Human Immunodeficiency VirusGenes, DominantGenes, ViralHIV InfectionsHIV-1HumansMaleMiceMutationRNA, ViralT-Lymphocytes, CytotoxicViral LoadVirus LatencyVirus Replication
2014
Attachment of Cell-Binding Ligands to Arginine-Rich Cell-Penetrating Peptides Enables Cytosolic Translocation of Complexed siRNA
Zeller S, Choi CS, Uchil PD, Ban HS, Siefert A, Fahmy TM, Mothes W, Lee SK, Kumar P. Attachment of Cell-Binding Ligands to Arginine-Rich Cell-Penetrating Peptides Enables Cytosolic Translocation of Complexed siRNA. Cell Chemical Biology 2014, 22: 50-62. PMID: 25544044, PMCID: PMC4320807, DOI: 10.1016/j.chembiol.2014.11.009.Peer-Reviewed Original Research
2008
T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice
Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner DL, Laouar A, Yao J, Haridas V, Habiro K, Yang YG, Jeong JH, Lee KY, Kim YH, Kim SW, Peipp M, Fey GH, Manjunath N, Shultz LD, Lee SK, Shankar P. T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice. Cell 2008, 134: 577-586. PMID: 18691745, PMCID: PMC2943428, DOI: 10.1016/j.cell.2008.06.034.Peer-Reviewed Original ResearchConceptsHIV infectionAntiviral siRNAsT cellsAnimal modelsCD4 T-cell countCD4 T-cell lossPeripheral blood mononuclear cellsSuppress HIV-1 infectionHu-HSC miceHu-PBL miceT-cell countsT cell lossHIV-1 infectionBlood mononuclear cellsNaive T cellsPreclinical animal modelsSuitable animal modelHumanized miceInfected miceMononuclear cellsSuppress viremiaCell countCell lossTherapeutic potentialHematopoietic stem cells