2024
Electron tomography visualization of HIV-1 virions trapped by fusion inhibitors to host cells in infected tissues
Ladinsky M, Zhu L, Ullah I, Uchil P, Kumar P, Kay M, Bjorkman P. Electron tomography visualization of HIV-1 virions trapped by fusion inhibitors to host cells in infected tissues. Journal Of Virology 2024, 98: e01432-24. PMID: 39475277, PMCID: PMC11575291, DOI: 10.1128/jvi.01432-24.Peer-Reviewed Original ResearchHIV-1 virionsHIV-1 target cellsHIV-1Fusion inhibitorsTarget cellsBone marrow/liver/thymus miceHIV-1 pseudovirionsCo-receptorHost cell membraneTZM-bl cellsPre-hairpin intermediateVascular endothelial cellsCell surfaceHumanized miceTZM-blCell membraneInfected tissuesEnvEndothelial cellsViral envelopeBind host receptorsHost receptorsInhibitorsCo-receptor proteinsPresence of virionsBeta Spike-Presenting SARS-CoV-2 Virus-like Particle Vaccine Confers Broad Protection against Other VOCs in Mice
Ullah I, Symmes K, Keita K, Zhu L, Grunst M, Li W, Mothes W, Kumar P, Uchil P. Beta Spike-Presenting SARS-CoV-2 Virus-like Particle Vaccine Confers Broad Protection against Other VOCs in Mice. Vaccines 2024, 12: 1007. PMID: 39340037, PMCID: PMC11435481, DOI: 10.3390/vaccines12091007.Peer-Reviewed Original ResearchImmune responseVirus-like particlesBeta spikesCross-protective immune responsesSARS-CoV-2 immunitySARS-CoV-2Effective immune responseEffective humoral immune responseHumoral immune responseAncestral spikeT cellsVaccination regimenSARS-CoV-2 virus-like particlesVaccine platformMouse modelVariant spike proteinsOmicron spikeBeta variantDisease burdenNon-infectiousReduce virus spreadImmunityVariant spikesFusion glycoproteinSpike proteinProof-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 formulationBioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens
Ullah I, Escudie F, Scandale I, Gilani Z, Gendron-Lepage G, Gaudette F, Mowbray C, Fraisse L, Bazin R, Finzi A, Mothes W, Kumar P, Chatelain E, Uchil P. Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens. IScience 2024, 27: 109049. PMID: 38361624, PMCID: PMC10867665, DOI: 10.1016/j.isci.2024.109049.Peer-Reviewed Original ResearchDirect-acting antiviralsEfficacy of direct-acting antiviralsVirus clearanceSARS-CoV-2Bioluminescence imagingSuppressed viral loadK18-hACE2 miceRapid virus clearanceNeutralizing antibody treatmentSARS-CoV-2 clearanceEvaluate therapeutic efficacyCOVID-19 convalescent plasmaMonotherapy regimensCombinatorial regimensAntibody treatmentViral loadSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Lung pathologyPandemic potentialRespiratory syndrome coronavirus 2Therapeutic arsenalConvalescent plasmaTreatment efficacySyndrome coronavirus 2
2023
Immunogenicity and Pre-Clinical Efficacy of an OMV-Based SARS-CoV-2 Vaccine
Grandi A, Tomasi M, Ullah I, Bertelli C, Vanzo T, Accordini S, Gagliardi A, Zanella I, Benedet M, Corbellari R, Di Lascio G, Tamburini S, Caproni E, Croia L, RavĂ M, Fumagalli V, Di Lucia P, Marotta D, Sala E, Iannacone M, Kumar P, Mothes W, Uchil P, Cherepanov P, Bolognesi M, Pizzato M, Grandi G. Immunogenicity and Pre-Clinical Efficacy of an OMV-Based SARS-CoV-2 Vaccine. Vaccines 2023, 11: 1546. PMID: 37896949, PMCID: PMC10610814, DOI: 10.3390/vaccines11101546.Peer-Reviewed Original ResearchSARS-CoV-2 vaccinesSARS-CoV-2Outer membrane vesiclesImmune responseSARS-CoV-2 elicitsSARS-CoV-2 variantsPotent immune responsesEffective immune responsePre-clinical efficacyDiverse SARS-CoV-2 variantsInherent adjuvanticityVaccinated miceIntranasal challengeVaccine dosesNeutralization titresEffective vaccineVirus infectionVaccination campaignHeterologous antigensVaccineVirus replicationSpike proteinInfectivity assaysTitresPotential needVaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models
Lorenzo M, MarĂn-LĂłpez A, Chiem K, Jimenez-Cabello L, Ullah I, Utrilla-Trigo S, Calvo-Pinilla E, Lorenzo G, Moreno S, Ye C, Park J, MatĂa A, Brun A, Sánchez-Puig J, Nogales A, Mothes W, Uchil P, Kumar P, Ortego J, Fikrig E, Martinez-Sobrido L, Blasco R. Vaccinia Virus Strain MVA Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Glycoprotein Induces Robust Protection and Prevents Brain Infection in Mouse and Hamster Models. Vaccines 2023, 11: 1006. PMID: 37243110, PMCID: PMC10220993, DOI: 10.3390/vaccines11051006.Peer-Reviewed Original ResearchVaccine candidatesStrong T cell responsesAngiotensin-converting enzyme 2Prime-boost regimensT cell responsesFull-length SARS-CoV-2 spike proteinEffective COVID-19 vaccineGolden Syrian hamstersSARS-CoV-2 spike glycoproteinSARS-CoV-2 spike proteinCOVID-19 vaccineRecombinant MVA vaccinesSARS-CoV-2S proteinBrain infectionMVA vaccinesCell-cell fusionAmino acid substitutionsVaccine platformHamster modelEnzyme 2Recombinant MVAVaccine vectorAnimal modelsRobust immunity
2022
The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice
Ullah I, Beaudoin-Bussières G, Symmes K, Cloutier M, Ducas E, Tauzin A, Laumaea A, Grunst M, Dionne K, Richard J, Bégin P, Mothes W, Kumar P, Bazin R, Finzi A, Uchil P. The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice. Cell Reports Medicine 2022, 4: 100893. PMID: 36584683, PMCID: PMC9799175, DOI: 10.1016/j.xcrm.2022.100893.Peer-Reviewed Original ResearchConceptsCOVID-19 convalescent plasmaFc effector functionsSARS-CoV-2 controlFc effector activityInnate immune cellsCCP efficacyHACE2 miceConvalescent plasmaImmunoglobulin levelsPlasma therapyImmune cellsTreatment efficacyDelays mortalityIgG fractionFc functionLow neutralizingTherapySecond lineMortalityMicePlasma contributesEfficacyFC activityProphylaxisIgGMolecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD
Chen Y, Prévost J, Ullah I, Romero H, Lisi V, Tolbert W, Grover J, Ding S, Gong S, Beaudoin-Bussières G, Gasser R, Benlarbi M, Vézina D, Anand S, Chatterjee D, Goyette G, Grunst M, Yang Z, Bo Y, Zhou F, Béland K, Bai X, Zeher A, Huang R, Nguyen D, Sherburn R, Wu D, Piszczek G, Paré B, Matthies D, Xia D, Richard J, Kumar P, Mothes W, Côté M, Uchil P, Lavallée V, Smith M, Pazgier M, Haddad E, Finzi A. Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD. IScience 2022, 26: 105783. PMID: 36514310, PMCID: PMC9733284, DOI: 10.1016/j.isci.2022.105783.Peer-Reviewed Original ResearchReceptor-binding domainSARS-CoV-2 patientsK18-hACE2 micePlasma neutralization activitySARS-CoV-2 variantsSARS-CoV-2 spike receptor-binding domainSpike receptor-binding domainProphylactic administrationNAb responsesPediatric patientsPotent NAbsLethal challengeNeutralizing antibodiesNeutralization activityDelta VOCEffector activityAntiviral mechanismAntiviral activityClinical interventionsPatientsNAbsAntibodiesEpitopesMolecular determinantsMolecular basisOP 6.2 – 00195 Targeted genome engineering of human t cells in vivo for HIV cure
Kumar P, Beloor J, Krishnaswamy J, Ullah I, Uchil P. OP 6.2 – 00195 Targeted genome engineering of human t cells in vivo for HIV cure. Journal Of Virus Eradication 2022, 8: 100247. DOI: 10.1016/j.jve.2022.100247.Peer-Reviewed Original ResearchEngineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities
Chen Y, Sun L, Ullah I, Beaudoin-Bussières G, Anand SP, Hederman AP, Tolbert WD, Sherburn R, Nguyen DN, Marchitto L, Ding S, Wu D, Luo Y, Gottumukkala S, Moran S, Kumar P, Piszczek G, Mothes W, Ackerman ME, Finzi A, Uchil PD, Gonzalez FJ, Pazgier M. Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities. Science Advances 2022, 8: eabn4188. PMID: 35857504, PMCID: PMC9278865, DOI: 10.1126/sciadv.abn4188.Peer-Reviewed Original ResearchAngiotensin-converting enzyme 2Soluble angiotensin-converting enzyme 2Fc effector functionsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptorLethal SARS-CoV-2 infectionK18-hACE2 mouse modelSARS-CoV-2 infectionAntibody-dependent cellular cytotoxicitySARS-CoV-2 antiviralsFc effector activityCoV-2 infectionSARS-CoV-2 variantsHalf maximal inhibitory concentrationComplement depositionACE2-FcCellular cytotoxicityEnzyme 2Mouse modelTherapeutic activityInhibitory concentrationTherapeutic settingDirect neutralizationInfectionReceptorsEffect of neutralizationVE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry
Ding S, Ullah I, Gong SY, Grover J, Mohammadi M, Chen Y, Vézina D, Beaudoin-Bussières G, Verma VT, Goyette G, Gaudette F, Richard J, Yang D, Smith AB, Pazgier M, Côté M, Abrams C, Kumar P, Mothes W, Uchil P, Finzi A, Baron C. VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry. IScience 2022, 25: 104528. PMID: 35677392, PMCID: PMC9164512, DOI: 10.1016/j.isci.2022.104528.Peer-Reviewed Original ResearchSARS-CoV-2 infectionAuthentic SARS-CoV-2K18-hACE2 miceS-ACE2 interactionsDevelopment of immunotherapySARS-CoV-2 spikeSARS-CoV-2SARS-CoV-1Prophylactic treatmentLow micromolar concentrationsViral replicationACE2 receptorPseudoviral particlesViral entrySpike glycoproteinPotential targetCOVID-19Drug developmentInfectionACE2 interfaceHost cellsMicromolar concentrationsReceptorsTreatmentRBDA 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
Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern
Li W, Chen Y, Prévost J, Ullah I, Lu M, Gong SY, Tauzin A, Gasser R, Vézina D, Anand SP, Goyette G, Chaterjee D, Ding S, Tolbert WD, Grunst MW, Bo Y, Zhang S, Richard J, Zhou F, Huang RK, Esser L, Zeher A, Côté M, Kumar P, Sodroski J, Xia D, Uchil PD, Pazgier M, Finzi A, Mothes W. Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern. Cell Reports 2021, 38: 110210. PMID: 34971573, PMCID: PMC8673750, DOI: 10.1016/j.celrep.2021.110210.Peer-Reviewed Original ResearchVariants of concernProtective immune responseReceptor-binding domainImmune responseImmunogen designSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Syndrome coronavirus 2Mode of actionSARS-CoV-2 spikeSARS-CoV-2Vaccine immunogen designAntibody therapyCoronavirus 2Β-coronavirusMonoclonal antibodiesS1 subunitS2 subunitAntibodiesTherapyVariantsLive 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 neutralizationInfectionAntibodies
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 signalIntroducing 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 ResearchElectroporation
Kumar P, Nagarajan A, Uchil PD. Electroporation. Cold Spring Harbor Protocols 2019, 2019: pdb.top096271. PMID: 31262965, DOI: 10.1101/pdb.top096271.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 adherentLipofectinLipofection.
Kumar P, Nagarajan A, Uchil PD. Lipofection. Cold Spring Harbor Protocols 2019, 2019: pdb.top096248. PMID: 30824627, DOI: 10.1101/pdb.top096248.Peer-Reviewed Original Research
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