2024
Design 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 ResearchEpistatic 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 mechanismsDolutegravirMutationsIntegrase
2023
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. 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 membraneAntiviral 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 ResearchTemsavir 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
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 virionsAssociating 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
HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations
Ma X, Lu M, Gorman J, Terry DS, Hong X, Zhou Z, Zhao H, Altman RB, Arthos J, Blanchard SC, Kwong PD, Munro JB, Mothes W. HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations. ELife 2018, 7: e34271. PMID: 29561264, PMCID: PMC5896952, DOI: 10.7554/elife.34271.Peer-Reviewed Original Research
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 contactCD169LymphocytesCrystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env
Do Kwon Y, Pancera M, Acharya P, Georgiev I, Crooks E, Gorman J, Joyce M, Guttman M, Ma X, Narpala S, Soto C, Terry D, Yang Y, Zhou T, Ahlsen G, Bailer R, Chambers M, Chuang G, Doria-Rose N, Druz A, Hallen M, Harned A, Kirys T, Louder M, O'Dell S, Ofek G, Osawa K, Prabhakaran M, Sastry M, Stewart-Jones G, Stuckey J, Thomas P, Tittley T, Williams C, Zhang B, Zhao H, Zhou Z, Donald B, Lee L, Zolla-Pazner S, Baxa U, Schön A, Freire E, Shapiro L, Lee K, Arthos J, Munro J, Blanchard S, Mothes W, Binley J, McDermott A, Mascola J, Kwong P. Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nature Structural & Molecular Biology 2015, 22: 522-531. PMID: 26098315, PMCID: PMC4706170, DOI: 10.1038/nsmb.3051.Peer-Reviewed Original Research
2014
Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions
Munro JB, Gorman J, Ma X, Zhou Z, Arthos J, Burton DR, Koff WC, Courter JR, Smith AB, Kwong PD, Blanchard SC, Mothes W. Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science 2014, 346: 759-763. PMID: 25298114, PMCID: PMC4304640, DOI: 10.1126/science.1254426.Peer-Reviewed Original Research