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, e0143224. PMID: 39475277, 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 virionsCD4 downregulation precedes Env expression and protects HIV-1-infected cells from ADCC mediated by non-neutralizing antibodies.
Richard J, Sannier G, Zhu L, Prévost J, Marchitto L, Benlarbi M, Beaudoin-Bussières G, Kim H, Sun Y, Chatterjee D, Medjahed H, Bourassa C, Delgado G, Dubé M, Kirchhoff F, Hahn B, Kumar P, Kaufmann D, Finzi A. CD4 downregulation precedes Env expression and protects HIV-1-infected cells from ADCC mediated by non-neutralizing antibodies. MBio 2024, e0182724. PMID: 39373535, DOI: 10.1128/mbio.01827-24.Peer-Reviewed Original ResearchAntibody-dependent cellular cytotoxicityProductively infected cellsEnv-CD4 interactionNon-neutralizing antibodiesHIV-1CD4 downmodulationEnv expressionCellular cytotoxicityResistance to antibody-dependent cellular cytotoxicityHIV-1-infected humanized miceInfected cellsHIV-1 cure strategiesHIV-1 mRNA expressionHIV-1-infected cellsCD4+ T cellsHIV-1 envelope glycoproteinMRNA expressionADCC-mediating antibodiesNon-neutralizing AbsCell surface CD4HIV-1 isolatesImmunotherapy-based strategiesMultiparametric flow cytometryVirally infected cellsEffective immune responseBeta 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 proteinUnderstanding emerging and re-emerging viruses to facilitate pandemic preparedness
Zapatero-Belinchón F, Kumar P, Ott M, Schwartz O, Sigal A. Understanding emerging and re-emerging viruses to facilitate pandemic preparedness. Nature Microbiology 2024, 9: 2208-2211. PMID: 39198691, DOI: 10.1038/s41564-024-01789-5.Peer-Reviewed Original ResearchProof-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 formulationBlocking Fas signaling in adipose tissue ameliorates obesity-associated inflammation, insulin resistance, and hepatosteatosis
Beloor J, Ullah I, Kim J, Choi C, Kim S, Chung K, KR J, Yi Y, Rhim T, Kumar P, Lee S. Blocking Fas signaling in adipose tissue ameliorates obesity-associated inflammation, insulin resistance, and hepatosteatosis. Journal Of Pharmaceutical Investigation 2024, 54: 519-537. DOI: 10.1007/s40005-024-00668-9.Peer-Reviewed Original ResearchFas signalingMatrix-assisted laser desorption/ionization-time of flight spectrometryBlock Fas signalingNon-apoptotic signalsMatrix-assisted laser desorption/ionization-timeNon-apoptotic pathwaysAdipose tissue macrophagesHigh-fat diet-induced obese mouse modelImpaired insulin signalingInsulin resistanceDiet-induced obesity mouse modelDUTP nick end labeling assayRecruitment of adipose tissue macrophagesFas receptorInsulin signalingPeptide polymerizationNick end labeling assayTissue macrophagesAdipocyte apoptosisSuppress production of inflammatory cytokinesTerminal deoxynucleotidyl transferase dUTP nick end labeling assayReal-time PCRDeoxynucleotidyl transferase dUTP nick end labeling assayObese mouse modelGene expressionBioluminescence 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 2Cell surface RNAs control neutrophil recruitment
Zhang N, Tang W, Torres L, Wang X, Ajaj Y, Zhu L, Luan Y, Zhou H, Wang Y, Zhang D, Kurbatov V, Khan S, Kumar P, Hidalgo A, Wu D, Lu J. Cell surface RNAs control neutrophil recruitment. Cell 2024, 187: 846-860.e17. PMID: 38262409, PMCID: PMC10922858, DOI: 10.1016/j.cell.2023.12.033.Peer-Reviewed Original ResearchConceptsCell surfaceMammalian homologOuter cell surfaceRNA transportGlycan modificationsMammalian cellsSID-1Cellular functionsRecruitment to inflammatory sitesGlycoRNARNAMurine neutrophilsFunctional significanceNeutrophil recruitmentNeutrophil recruitment to inflammatory sitesBiological importanceCellsNeutrophil adhesionReduced neutrophil adhesionHomologyGlycansGenesInflammatory sitesRecruitmentEndothelial cellsSystemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer’s Disease
Kim S, Ullah I, Beloor J, Chung K, Kim J, Yi Y, Kang E, Yun G, Heo S, Pyun S, Kim S, Kumar P, Lee S. Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-β Accumulation in Alzheimer’s Disease. Biomaterials Research 2024, 28: 0027. PMID: 38868092, PMCID: PMC11168191, DOI: 10.34133/bmr.0027.Peer-Reviewed Original Research
2023
Cell Surface RNAs Control Neutrophil Function
Zhang N, Tang W, Torres L, Zhu L, Wang X, Ajaj Y, Wang Y, Zhang D, Kurbatov V, Zhou H, Luan Y, Kumar P, Hidalgo A, Wu D, Lu J. Cell Surface RNAs Control Neutrophil Function. Blood 2023, 142: 674. DOI: 10.1182/blood-2023-187570.Peer-Reviewed Original ResearchExtracellular RNaseCell surfaceTotal RNABona fide ligandsEndothelial cellsOuter cell surfaceTransendothelial migrationMammalian cellsSuch RNAsGlycan modificationsCellular RNAGlycoRNARNase digestionLive cellsRNAHematopoietic cellsRNase treatmentSimilar defectsIntegrin levelsConfocal microscopyRNaseGlycan fractionImportant functionsHomologuesRecombinant E-selectinHIV-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 ResearchImmunogenicity 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, Ravà 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 needExploiting 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 geneVaccinia 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, Marín-López A, Chiem K, Jimenez-Cabello L, Ullah I, Utrilla-Trigo S, Calvo-Pinilla E, Lorenzo G, Moreno S, Ye C, Park J, Matía 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 ResearchHIV-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 cellsNnAbsVirusVpuAdministrationEngineered 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 concentrationsReceptorsTreatmentRBD