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 formulationPrior Influenza Infection Mitigates SARS-CoV-2 Disease in Syrian Hamsters
Di Pietro C, Haberman A, Lindenbach B, Smith P, Bruscia E, Allore H, Vander Wyk B, Tyagi A, Zeiss C. Prior Influenza Infection Mitigates SARS-CoV-2 Disease in Syrian Hamsters. Viruses 2024, 16: 246. PMID: 38400021, PMCID: PMC10891789, DOI: 10.3390/v16020246.Peer-Reviewed Original ResearchConceptsTransient gene expressionSARS-CoV-2Viral replication pathwayReplication pathwayAntiviral pathwaysEndemism patternsUpregulation of innateGene expressionQuantitative RT-PCRMitigated weight lossDual-infected animalsSARS-CoV-2 viral loadSARS-CoV-2 infectionSyrian hamstersSeasonal infection ratesSARS-CoV-2 inoculationLungs of animalsIndividual virusesSARS-CoV-2 diseaseUpper respiratory tractH1N1 infectionRT-PCRBronchoalveolar lavageViral loadCytokine levels
2023
Astrovirus replication is dependent on induction of double-membrane vesicles through a PI3K-dependent, LC3-independent pathway
Bub T, Hargest V, Tan S, Smith M, Vazquez-Pagan A, Flerlage T, Brigleb P, Meliopoulos V, Lindenbach B, Ramanathan H, Cortez V, Crawford J, Schultz-Cherry S. Astrovirus replication is dependent on induction of double-membrane vesicles through a PI3K-dependent, LC3-independent pathway. Journal Of Virology 2023, 97: e01025-23. PMID: 37668367, PMCID: PMC10537808, DOI: 10.1128/jvi.01025-23.Peer-Reviewed Original ResearchConceptsAstrovirus infectionAstrovirus replicationPromising therapeutic optionPositive-sense RNA virus infectionPotential antiviral targetsRNA virusesRNA virus infectionCritical new evidenceGastrointestinal symptomsTherapeutic optionsPositive-sense RNA virusesVirus infectionTherapeutic interventionsAntiviral targetViral replicationDMV formationInfectionGenetic inhibitionReplication organellesHuman astrovirusPI3KPotential targetEarly componentPatientsAutophagy machinery
2022
The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures
Wan H, Adams RL, Lindenbach BD, Pyle AM. The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures. Journal Of Virology 2022, 96: e01946-21. PMID: 35353000, PMCID: PMC9044954, DOI: 10.1128/jvi.01946-21.Peer-Reviewed Original ResearchConceptsSecondary structure mapRNA genomeRNA structureTertiary structureProtein-coding genesPositive-strand RNA virusesRegulatory RNA structuresFull-length structureHCV RNA genomeValuable model systemRNA structural motifsSecondary structural elementsEvolutionary functional analysisLife cycleVirus life cycleCellular contextCorresponding transcriptsImportant human pathogenLong RNAsGenomeSame RNAGenomic RNAComprehensive atlasFunctional analysisFunctional importanceDe novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report
Gandhi S, Klein J, Robertson AJ, Peña-Hernández MA, Lin MJ, Roychoudhury P, Lu P, Fournier J, Ferguson D, Mohamed Bakhash SAK, Catherine Muenker M, Srivathsan A, Wunder EA, Kerantzas N, Wang W, Lindenbach B, Pyle A, Wilen CB, Ogbuagu O, Greninger AL, Iwasaki A, Schulz WL, Ko AI. De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report. Nature Communications 2022, 13: 1547. PMID: 35301314, PMCID: PMC8930970, DOI: 10.1038/s41467-022-29104-y.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionVirologic responsePersistent SARS-CoV-2 infectionResistance mutationsPre-treatment specimensB-cell deficiencyRemdesivir resistanceRemdesivir therapyViral sheddingCase reportAntiviral agentsPatientsCombinatorial therapyInfectionTherapyWhole-genome sequencingTreatmentImportance of monitoringDe novo emergenceFold increaseRNA-dependent RNA polymeraseNovo emergencePotential benefitsMutationsIndolent
2021
Placenta-derived interferon-stimulated gene 20 controls ZIKA virus infection
Ding J, Aldo P, Roberts CM, Stabach P, Liu H, You Y, Qiu X, Jeong J, Maxwell A, Lindenbach B, Braddock D, Liao A, Mor G. Placenta-derived interferon-stimulated gene 20 controls ZIKA virus infection. EMBO Reports 2021, 22: embr202152450. PMID: 34405956, PMCID: PMC8490983, DOI: 10.15252/embr.202152450.Peer-Reviewed Original ResearchConceptsZika virus infectionVirus infectionTrophoblast cellsPotential immune modulatory functionsInterferon-stimulated gene 20Anti-viral treatmentHigh-risk populationImmune modulatory functionsAnti-viral responseZika viral infectionImportance of preventionPregnant womenReplacement therapyViral infectionFetal developmentZika virusViral titersModulatory functionViral replicationInfectionAdverse effectsGene 20PregnancyPlacentaRNA viruses
2016
Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
Onorati M, Li Z, Liu F, Sousa AMM, Nakagawa N, Li M, Dell’Anno M, Gulden FO, Pochareddy S, Tebbenkamp AT, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Reports 2016, 16: 2576-2592. PMID: 27568284, PMCID: PMC5135012, DOI: 10.1016/j.celrep.2016.08.038.Peer-Reviewed Original ResearchMeSH KeywordsAxl Receptor Tyrosine KinaseBrainCell DeathCentrosomeFetusGene Expression ProfilingHumansImmunity, InnateMicrocephalyMitochondriaMitosisNeocortexNeural Stem CellsNeuroepithelial CellsNeurogliaNeuronsNeuroprotective AgentsNucleosidesPhosphorylationProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSpinal CordTranscription, GeneticVirus ReplicationZika VirusZika Virus InfectionConceptsRadial glial cellsNES cellsNeuroepithelial stem cellsZIKV infectionFetal brain slicesStem cellsEarly human neurodevelopmentHuman neuroepithelial stem cellsHuman neural stem cellsCell deathSingle-cell RNA-seqNeural stem cellsNeurodevelopment defectsZIKV replicationGlial cellsBrain slicesPotential treatmentRadial gliaZika virusPhospho-TBK1Neurodevelopmental defectsRNA-seqSupernumerary centrosomesNucleoside analoguesHuman neurodevelopment
2015
Hepatitis C Virus RNA Replication Depends on Specific Cis- and Trans-Acting Activities of Viral Nonstructural Proteins
Kazakov T, Yang F, Ramanathan HN, Kohlway A, Diamond MS, Lindenbach BD. Hepatitis C Virus RNA Replication Depends on Specific Cis- and Trans-Acting Activities of Viral Nonstructural Proteins. PLOS Pathogens 2015, 11: e1004817. PMID: 25875808, PMCID: PMC4395149, DOI: 10.1371/journal.ppat.1004817.Peer-Reviewed Original ResearchConceptsRNA bindingRNA replicationPositive-strand RNA virus replicationComplementation group analysisPositive-strand RNA virusesPolymerase activityRNA virus replicationNS3 helicase domainViral nonstructural proteinsCis-acting roleGene functionVirus RNA replicationHelicase domainSpecific cisReplicase geneGenome replicationReplicase assemblyLethal mutationsNonstructural genesNTPase activityStudy of cisNonstructural proteinsRNA virusesSynthetic mRNAFunctional linkage
2013
The ins and outs of hepatitis C virus entry and assembly
Lindenbach BD, Rice CM. The ins and outs of hepatitis C virus entry and assembly. Nature Reviews Microbiology 2013, 11: 688-700. PMID: 24018384, PMCID: PMC3897199, DOI: 10.1038/nrmicro3098.Peer-Reviewed Original ResearchConceptsHCV particlesRNA virusesPositive-strand RNA virusesSignal transduction eventsSerum lipoproteinsCell surface proteinsHepatitis C Virus EntryNumerous cell surface proteinsNon-structural proteinsNew structural informationC virus entrySecretory pathwayTransduction eventsUncharacterized mechanismMembrane fusionHCV particle assemblyCellular processingSurface proteinsC virus
2011
Trafficking of Hepatitis C Virus Core Protein during Virus Particle Assembly
Counihan NA, Rawlinson SM, Lindenbach BD. Trafficking of Hepatitis C Virus Core Protein during Virus Particle Assembly. PLOS Pathogens 2011, 7: e1002302. PMID: 22028650, PMCID: PMC3197604, DOI: 10.1371/journal.ppat.1002302.Peer-Reviewed Original ResearchStructural Insights into RNA Recognition by RIG-I
Luo D, Ding SC, Vela A, Kohlway A, Lindenbach BD, Pyle AM. Structural Insights into RNA Recognition by RIG-I. Cell 2011, 147: 409-422. PMID: 22000018, PMCID: PMC3222294, DOI: 10.1016/j.cell.2011.09.023.Peer-Reviewed Original ResearchConceptsPathogen-associated molecular patternsTerminal regulatory domainProtein familyRegulatory domainProtein domainsInsertion domainRNA recognitionMolecular basisATP hydrolysisStructural insightsIntracellular RIGRNAMolecular patternsMotor domainLike receptorsAntiviral immune responseViral RNANanomechanical FunctionDomainHelicasesComplex interplayHelicaseCladeHel2DsRNA
2010
Hepatitis C Virus NS2 Coordinates Virus Particle Assembly through Physical Interactions with the E1-E2 Glycoprotein and NS3-NS4A Enzyme Complexes
Stapleford KA, Lindenbach BD. Hepatitis C Virus NS2 Coordinates Virus Particle Assembly through Physical Interactions with the E1-E2 Glycoprotein and NS3-NS4A Enzyme Complexes. Journal Of Virology 2010, 85: 1706-1717. PMID: 21147927, PMCID: PMC3028914, DOI: 10.1128/jvi.02268-10.Peer-Reviewed Original ResearchConceptsProtein complexesBlue native polyacrylamide gel electrophoresisEnzyme complexHepatitis C virus NS2Early secretory pathwayProtein complex formationHepatitis C Virus NS2 ProteinViral proteinsNative polyacrylamide gel electrophoresisParticle assemblyHCV particle assemblyVirus particle assemblyGenetic interactionsSecretory pathwayComplex interactsCentral organizing roleInteraction partnersE1-E2 glycoproteinsNS2 proteinVirus assemblyNonstructural proteinsPolyacrylamide gel electrophoresisP7 proteinProteinOrganizing roleThe Acidic Domain of Hepatitis C Virus NS4A Contributes to RNA Replication and Virus Particle Assembly
Phan T, Kohlway A, Dimberu P, Pyle AM, Lindenbach BD. The Acidic Domain of Hepatitis C Virus NS4A Contributes to RNA Replication and Virus Particle Assembly. Journal Of Virology 2010, 85: 1193-1204. PMID: 21047963, PMCID: PMC3020511, DOI: 10.1128/jvi.01889-10.Peer-Reviewed Original ResearchConceptsVirus particle assemblyAcidic domainGenome replicationAssembly defectsEnzyme complexSevere defectsMembrane-bound enzyme complexRNA replicationTerminal acidic domainNS3-4AAlanine-scanning mutagenesisSecond-site mutationsViral genome replicationHepatitis C virus (HCV) NS3-4AGenetic interactionsRNA helicaseParticle assemblyReplication defectScanning mutagenesisMutant formsVirus assemblySerine proteasesEnzymatic activityATPase activityMutants
2009
Hepatitis C Virus NS2 Protein Contributes to Virus Particle Assembly via Opposing Epistatic Interactions with the E1-E2 Glycoprotein and NS3-NS4A Enzyme Complexes
Phan T, Beran RK, Peters C, Lorenz IC, Lindenbach BD. Hepatitis C Virus NS2 Protein Contributes to Virus Particle Assembly via Opposing Epistatic Interactions with the E1-E2 Glycoprotein and NS3-NS4A Enzyme Complexes. Journal Of Virology 2009, 83: 8379-8395. PMID: 19515772, PMCID: PMC2738163, DOI: 10.1128/jvi.00891-09.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionCarrier ProteinsHepacivirusHumansIntracellular Signaling Peptides and ProteinsModels, MolecularMolecular Sequence DataMutation, MissenseProtein BindingProtein Interaction MappingSuppression, GeneticViral Envelope ProteinsViral Nonstructural ProteinsViral ProteinsVirus AssemblyConceptsHepatitis C Virus NS2 ProteinVirus particle assemblyNS2 proteinVirus assemblyReverse genetic analysisForward genetic selectionSecond-site mutationsNS2 mutantsSuppressor mutationsRNA bindingEpistatic interactionsBiochemical experimentsGenetic analysisEnzyme complexSevere defectsNonstructural proteinsGenetic selectionParticle assemblyRNA replicationCell culture systemMutationsNS3-NS4AProteinMutantsMutual exclusivity
2006
Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro
Lindenbach BD, Meuleman P, Ploss A, Vanwolleghem T, Syder AJ, McKeating JA, Lanford RE, Feinstone SM, Major ME, Leroux-Roels G, Rice CM. Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 3805-3809. PMID: 16484368, PMCID: PMC1533780, DOI: 10.1073/pnas.0511218103.Peer-Reviewed Original ResearchConceptsHepatitis C virusC virusCell culture-grown hepatitis C virusChronic liver diseaseHuman liver graftsHCV culture systemsHCV life cycleLong-term infectionLiver graftsLiver diseaseCurrent therapiesHepatocellular carcinomaCell culturesInfectious virusImproved infectivityMajor causeViral infectivityVivo cultureHCVccVirusInfectious cloneVivo dissectionInfectivityCulture systemCirrhosis
2005
Unravelling hepatitis C virus replication from genome to function
Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005, 436: 933-938. PMID: 16107832, DOI: 10.1038/nature04077.Peer-Reviewed Original ResearchComplete Replication of Hepatitis C Virus in Cell Culture
Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. Complete Replication of Hepatitis C Virus in Cell Culture. Science 2005, 309: 623-626. PMID: 15947137, DOI: 10.1126/science.1114016.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, ViralAntigens, CDAntiviral AgentsCell Line, TumorCentrifugation, Density GradientCulture Media, ConditionedGenome, ViralHepacivirusHumansInterferon-alphaMutationNeutralization TestsRepliconRNA, ViralSerial PassageTetraspanin 28TransfectionViral Envelope ProteinsViral Nonstructural ProteinsVirionVirus CultivationVirus ReplicationConceptsHepatitis C virus (HCV) life cyclePutative HCV receptorFull-length HCV genomeHepatitis C virusViral glycoprotein E2Cell culturesVirus particlesHCV receptorsC virusVirus life cycleHCV genomeGlycoprotein E2Important human pathogenAntiviral compoundsImproved antiviralsViral entryMonoclonal antibodiesCellular expressionInfectious unitsHuman pathogensVitro systemHCVccAntiviralsReplication
1994
Processing in the hepatitis C virus E2-NS2 region: identification of p7 and two distinct E2-specific products with different C termini
Lin C, Lindenbach B, Prágai B, McCourt D, Rice C. Processing in the hepatitis C virus E2-NS2 region: identification of p7 and two distinct E2-specific products with different C termini. Journal Of Virology 1994, 68: 5063-5073. PMID: 7518529, PMCID: PMC236449, DOI: 10.1128/jvi.68.8.5063-5073.1994.Peer-Reviewed Original Research