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 formulationEpistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors
Hikichi Y, Grover J, Schäfer A, Mothes W, Freed E. Epistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors. Science Advances 2024, 10: eadn0042. PMID: 38427738, PMCID: PMC10906922, DOI: 10.1126/sciadv.adn0042.Peer-Reviewed Original ResearchConceptsIntegrase strand transfer inhibitorsClasses of antiretroviralsHuman immunodeficiency virusStrand transfer inhibitorsHIV-1Env mutationsTransfer inhibitorsIntegrase strand transfer inhibitor dolutegravirHIV-1 escapeResistance to dolutegravirResistance to antiretroviralsAbsence of resistance mutationsClasses of drugsCell-cell transferVirological failureImmunodeficiency virusResistance mutationsGene mutationsEnvelope glycoproteinAntiretroviralsEnvResistance mechanismsDolutegravirMutationsIntegraseViral spike-receptor interactions monitored by cryo-electron tomograpy on membranes
Mothes W, Li W, Grunst M, Qin Z, Nand E. Viral spike-receptor interactions monitored by cryo-electron tomograpy on membranes. Biophysical Journal 2024, 123: 24a. DOI: 10.1016/j.bpj.2023.11.251.Peer-Reviewed Original ResearchBioluminescence 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 2Bioorthogonal click labeling of an amber-free HIV-1 provirus for in-virus single molecule imaging
Ao Y, Grover J, Gifford L, Han Y, Zhong G, Katte R, Li W, Bhattacharjee R, Zhang B, Sauve S, Qin W, Ghimire D, Haque M, Arthos J, Moradi M, Mothes W, Lemke E, Kwong P, Melikyan G, Lu M. Bioorthogonal click labeling of an amber-free HIV-1 provirus for in-virus single molecule imaging. Cell Chemical Biology 2024, 31: 487-501.e7. PMID: 38232732, PMCID: PMC10960674, DOI: 10.1016/j.chembiol.2023.12.017.Peer-Reviewed Original ResearchHIV-1Human immunodeficiency virus-1HIV-1 provirusMinimally invasive approachImmunodeficiency virus-1HIV-1 systemInvasive approachImmune evasionEnvVirus 1Virus entryStudies of virus entryCell entrySingle-molecule Forster resonance energy transferStructural dynamicsSingle molecule imagingMultiple conformational statesForster resonance energy transferCellsClick chemistryVirion internalizationResonance energy transferMolecule imagingEnergy transferLabeling of proteins
2023
Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy–Treated Individuals With Undetectable Viremia
Benlarbi M, Richard J, Bourassa C, Tolbert W, Chartrand-Lefebvre C, Gendron-Lepage G, Sylla M, El-Far M, Messier-Peet M, Guertin C, Turcotte I, Fromentin R, Verly M, Prévost J, Clark A, Mothes W, Kaufmann D, Maldarelli F, Chomont N, Bégin P, Tremblay C, Baril J, Trottier B, Trottier S, Duerr R, Pazgier M, Durand M, Finzi A. Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy–Treated Individuals With Undetectable Viremia. The Journal Of Infectious Diseases 2023, 229: 763-774. PMID: 38035854, PMCID: PMC10938206, DOI: 10.1093/infdis/jiad503.Peer-Reviewed Original ResearchImmune dysfunctionAntiretroviral therapyUndetectable viremiaChronic inflammationAtherosclerotic plaquesSubclinical coronary artery diseaseSub-clinical cardiovascular diseaseCoronary artery diseasePro-inflammatory cytokinesCross-sectional assessmentCanadian HIVCD4 depletionCD4 countCD8 ratioDetectable viremiaArtery diseaseIL-6Soluble gp120Cardiovascular diseaseGp120 subunitImmunomodulatory propertiesAging CohortInflammationViremiaSgp120HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes
Li W, Qin Z, Nand E, Grunst M, Grover J, Bess J, Lifson J, Zwick M, Tagare H, Uchil P, Mothes W. HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes. Nature 2023, 623: 1026-1033. PMID: 37993716, PMCID: PMC10686830, DOI: 10.1038/s41586-023-06762-6.Peer-Reviewed Original ResearchConceptsHIV-1 Env trimersCD4 moleculeHuman immunodeficiency virus-1 (HIV-1) infectionEnv trimersAntibody-mediated immune responsesEnv-CD4 interactionVirus-1 infectionVaccine immunogen designViral envelope glycoproteinsHIV-1Immune responseCD4 receptorImmunogen designEnvelope glycoproteinVirus-like particlesCD4EnvHost cell membraneImmunogenicity 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 needAntiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
Leonhardt S, Purdy M, Grover J, Yang Z, Poulos S, McIntire W, Tatham E, Erramilli S, Nosol K, Lai K, Ding S, Lu M, Uchil P, Finzi A, Rein A, Kossiakoff A, Mothes W, Yeager M. Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry. Nature Communications 2023, 14: 4368. PMID: 37474505, PMCID: PMC10359404, DOI: 10.1038/s41467-023-39262-2.Peer-Reviewed Original ResearchPLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factorsVaccinia 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 immunityTemsavir blocks the immunomodulatory activities of HIV-1 soluble gp120
Richard J, Prévost J, Bourassa C, Brassard N, Boutin M, Benlarbi M, Goyette G, Medjahed H, Gendron-Lepage G, Gaudette F, Chen H, Tolbert W, Smith A, Pazgier M, Dubé M, Clark A, Mothes W, Kaufmann D, Finzi A. Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120. Cell Chemical Biology 2023, 30: 540-552.e6. PMID: 36958337, PMCID: PMC10198848, DOI: 10.1016/j.chembiol.2023.03.003.Peer-Reviewed Original ResearchConceptsAntibody-dependent cellular cytotoxicityUninfected bystander CD4Gp120-CD4 interactionCytokine burstBystander CD4Immunomodulatory activityMultiple immune cellsHIV-1 attachment inhibitorsOverall antigenicityADCC responsesClinical benefitSoluble gp120Immune cellsCellular cytotoxicityAttachment inhibitorsCD4 interactionGp120 bindsCD4Gp120Viral entryEnvelope glycoproteinCD4 downregulationTemsavirCellsAntigenicity
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 basisSARS-Cov-2 variants of concern decelerate the dynamics of spike open conformation as an evolutionary strategy
Yang Z, Han Y, Ding S, Finzi A, Mothes W, Lu M. SARS-Cov-2 variants of concern decelerate the dynamics of spike open conformation as an evolutionary strategy. Biophysical Journal 2022, 121: 39a. PMCID: PMC8833081, DOI: 10.1016/j.bpj.2021.11.2500.Peer-Reviewed Original Research
2021
Real-Time Conformational Dynamics of SARS-CoV-2 Spikes on Virus Particles
Lu M, Uchil P, Li W, Terry D, Gorman J, Zhang B, Zhou T, Ding S, Liu L, Ho D, Mascola J, Finzi A, Kwong P, Blanchard S, Mothes W. Real-Time Conformational Dynamics of SARS-CoV-2 Spikes on Virus Particles. Biophysical Journal 2021, 120: 276a. PMCID: PMC7879775, DOI: 10.1016/j.bpj.2020.11.1757.Peer-Reviewed Original Research
2019
Chapter Eight Illuminating the virus life cycle with single-molecule FRET imaging
Lu M, Ma X, Mothes W. Chapter Eight Illuminating the virus life cycle with single-molecule FRET imaging. Advances In Virus Research 2019, 105: 239-273. PMID: 31522706, PMCID: PMC7246055, DOI: 10.1016/bs.aivir.2019.07.004.Peer-Reviewed Original ResearchConceptsVirus life cycleMolecular mechanismsViral proteinsSingle-molecule FRETBiological moleculesPrecise molecular mechanismsFörster resonance energy transfer (FRET) imagingLife cycleConformational dynamicsReal-time imagingEnergetics of transitionsNovel antiviral therapiesStructural intermediatesConformational changesConformational statesNative stateSmFRETRelevant conditionsElegant experimental designsAsymmetric intermediatesIntermediatesViral fusionViral glycoproteinsStructural methodsIntact virionsIn vivo Imaging-Driven Approaches to Study Virus Dissemination and Pathogenesis
Uchil PD, Haugh KA, Pi R, Mothes W. In vivo Imaging-Driven Approaches to Study Virus Dissemination and Pathogenesis. Annual Review Of Virology 2019, 6: 1-24. PMID: 31283440, PMCID: PMC7217087, DOI: 10.1146/annurev-virology-101416-041429.Peer-Reviewed Original ResearchAssociating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET
Lu M, Ma X, Castillo-Menendez LR, Gorman J, Alsahafi N, Ermel U, Terry DS, Chambers M, Peng D, Zhang B, Zhou T, Reichard N, Wang K, Grover JR, Carman BP, Gardner MR, Nikić-Spiegel I, Sugawara A, Arthos J, Lemke EA, Smith AB, Farzan M, Abrams C, Munro JB, McDermott AB, Finzi A, Kwong PD, Blanchard SC, Sodroski JG, Mothes W. Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET. Nature 2019, 568: 415-419. PMID: 30971821, PMCID: PMC6655592, DOI: 10.1038/s41586-019-1101-y.Peer-Reviewed Original ResearchConceptsSingle-molecule fluorescence resonance energy transferCryo-electron microscopy studiesHigh-resolution structuresFluorescence resonance energy transferState 1 conformationProline substitutionConformational statesResonance energy transferDisulfide bondsCell entryIntermediate conformationsReceptor moleculesGlycoprotein structureStructural studiesIntact virionsViral EnvCD4 receptor moleculeIntact virusConformationState 2TrimerState 1
2018
A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus
Uchil PD, Pi R, Haugh KA, Ladinsky MS, Ventura JD, Barrett BS, Santiago ML, Bjorkman PJ, Kassiotis G, Sewald X, Mothes W. A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus. Cell Host & Microbe 2018, 25: 87-100.e10. PMID: 30595553, PMCID: PMC6331384, DOI: 10.1016/j.chom.2018.11.011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesCell ProliferationDendritic CellsDisease Models, AnimalErythroblastsFemaleInterferon Type ILectinsLymph NodesMacrophagesMaleMiceMice, Inbred BALB CMice, Inbred C57BLProtective AgentsRetroviridaeRetroviridae InfectionsSialic Acid Binding Ig-like Lectin 1SpleenT-Lymphocytes, CytotoxicViral LoadConceptsCD169/SiglecEffective cytotoxic T lymphocyte (CTL) responseProtective roleCytotoxic T lymphocyte responsesLymph node infectionT lymphocyte responsesHigh viral loadSusceptible mouse strainsMarginal zone metallophilic macrophagesPermissive lymphocytesCytotoxic CD8Lymphocyte responsesViral loadSubcapsular sinusComplex infectionMurine modelViral disseminationMetallophilic macrophagesRed pulpCell responsesSystemic spreadMouse strainsPathogenesisCells 1CD169