2025
The conserved HIV-1 spacer peptide 2 triggers matrix lattice maturation
Stacey J, HrebĂk D, Nand E, Shetty S, Qu K, Boicu M, Anders-Ă–sswein M, Uchil P, Dick R, Mothes W, Kräusslich H, MĂĽller B, Briggs J. The conserved HIV-1 spacer peptide 2 triggers matrix lattice maturation. Nature 2025, 1-7. PMID: 40011770, DOI: 10.1038/s41586-025-08624-9.Peer-Reviewed Original ResearchSpacer peptide 2Membrane-binding domainVirus particlesProtein-protein interfacesCleavage site mutantsHigh-resolution structuresFusion of virusImmature virus particlesHIV-1Site mutantsProteolytic cleavageFunctional domainsHuman immunodeficiency virus type 1Bound lipidsImmunodeficiency virus type 1Infectious virionsHIV-1 componentsStructural polyprotein GagMature latticeProtein latticeVirus type 1Structural maturationMonolayers in vitroPeptide 2Polyprotein GagAuthor Correction: HIV-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. Author Correction: HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes. Nature 2025, 639: e15-e15. PMID: 39994465, PMCID: PMC11903299, DOI: 10.1038/s41586-025-08802-9.Peer-Reviewed Original ResearchBPS2025 - Structure and inhibition of SARS-CoV-2 spike refolding in membranes
Mothes W, Grunst M, Qin Z, Dodero-Rojas E, Ding S, Prevost J, Chen Y, Hu Y, Pazgier M, Wu S, Xie X, Finzi A, Onuchic J, Whitford P, Li W. BPS2025 - Structure and inhibition of SARS-CoV-2 spike refolding in membranes. Biophysical Journal 2025, 124: 580a. DOI: 10.1016/j.bpj.2024.11.3011.Peer-Reviewed Original ResearchCorrection for Kajaste-Rudnitski et al., “TRIM22 Inhibits HIV-1 Transcription Independently of Its E3 Ubiquitin Ligase Activity, Tat, and NF-κB-Responsive Long Terminal Repeat Elements”
Kajaste-Rudnitski A, Marelli S, Pultrone C, Pertel T, Uchil P, Mechti N, Mothes W, Poli G, Luban J, Vicenzi E. Correction for Kajaste-Rudnitski et al., “TRIM22 Inhibits HIV-1 Transcription Independently of Its E3 Ubiquitin Ligase Activity, Tat, and NF-κB-Responsive Long Terminal Repeat Elements”. Journal Of Virology 2025, 99: e02071-24. PMID: 39868830, PMCID: PMC11853098, DOI: 10.1128/jvi.02071-24.Peer-Reviewed Original Research
2024
Inducible cell lines producing replication-defective human immunodeficiency virus particles containing envelope glycoproteins stabilized in a pretriggered conformation
Ding H, Nguyen H, Li W, Deshpande A, Zhang S, Jiang F, Zhang Z, Anang S, Mothes W, Sodroski J, Kappes J. Inducible cell lines producing replication-defective human immunodeficiency virus particles containing envelope glycoproteins stabilized in a pretriggered conformation. Journal Of Virology 2024, 98: e01720-24. PMID: 39508605, PMCID: PMC11650979, DOI: 10.1128/jvi.01720-24.Peer-Reviewed Original ResearchHuman immunodeficiency virusEnv trimersNeutralizing antibodiesHIV-1Virus-like particlesEnvelope glycoproteinEnv conformationImmunodeficiency virusInducible cell linesCell linesImmune systemEffective HIV/AIDS vaccineHIV-1 persistenceHuman immunodeficiency virus particlesEnvelope glycoprotein spikeHIV-1 EnvPoorly neutralizing antibodiesHIV-like particlesHIV-1 particlesDefective virus-like particlesHost immune systemEnv immunogensHIV/AIDS vaccineCreation of stable cell linesHost cell receptorsThe KT Jeang retrovirology prize 2024: Walther Mothes
Mothes W. The KT Jeang retrovirology prize 2024: Walther Mothes. Retrovirology 2024, 21: 16. PMID: 39449025, PMCID: PMC11515334, DOI: 10.1186/s12977-024-00649-8.Peer-Reviewed Original ResearchBeta 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 proteinStructure and inhibition of SARS-CoV-2 spike refolding in membranes
Grunst M, Qin Z, Dodero-Rojas E, Ding S, Prévost J, Chen Y, Hu Y, Pazgier M, Wu S, Xie X, Finzi A, Onuchic J, Whitford P, Mothes W, Li W. Structure and inhibition of SARS-CoV-2 spike refolding in membranes. Science 2024, 385: 757-765. PMID: 39146425, PMCID: PMC11449073, DOI: 10.1126/science.adn5658.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2Antibodies, NeutralizingAntibodies, ViralBetacoronavirusCell MembraneCOVID-19Cryoelectron MicroscopyElectron Microscope TomographyHumansMolecular Dynamics SimulationPeptidyl-Dipeptidase AProtein DomainsProtein MultimerizationProtein RefoldingSARS-CoV-2Spike Glycoprotein, CoronavirusVirus InternalizationDesign of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation
Zhang P, Gorman J, Tsybovsky Y, Lu M, Liu Q, Gopan V, Singh M, Lin Y, Miao H, Seo Y, Kwon A, Olia A, Chuang G, Geng H, Lai Y, Zhou T, Mascola J, Mothes W, Kwong P, Lusso P. Design of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation. Cell Reports 2024, 43: 114518. PMID: 39028623, PMCID: PMC11459465, DOI: 10.1016/j.celrep.2024.114518.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 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, 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 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, 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
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