Featured Publications
Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Gale M, Li Y, Cao J, Liu ZZ, Holmbeck MA, Zhang M, Lang SM, Wu L, Do Carmo M, Gupta S, Aoshima K, DiGiovanna MP, Stern DF, Rimm DL, Shadel GS, Chen X, Yan Q. Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition. Cancer Research 2020, 80: 524-535. PMID: 31690671, PMCID: PMC7002225, DOI: 10.1158/0008-5472.can-18-3985.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBreast NeoplasmsCell ProliferationDrug Resistance, NeoplasmEnzyme InhibitorsFemaleHumansMiceMice, Inbred NODMice, SCIDMitochondrial Proton-Translocating ATPasesOligomycinsReceptor, ErbB-2TrastuzumabTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsResistant cellsHER2-Targeted TherapyTrastuzumab-resistant tumorsNew therapeutic strategiesNovel potential targetDrug-free mediumAntibody therapySynthase inhibitionLow doseTherapeutic strategiesTrastuzumabBreast tumorsHER2TherapyAcquired ResistanceTumorsPotential targetMitochondrial respirationCellsSelective dependencyInhibitionMinimal changesNovel vulnerabilitiesATP synthase inhibitionOligomycin AMitochondrial DNA stress primes the antiviral innate immune response
West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA, Kaech SM, Smiley JR, Means RE, Iwasaki A, Shadel GS. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 2015, 520: 553-557. PMID: 25642965, PMCID: PMC4409480, DOI: 10.1038/nature14156.Peer-Reviewed Original Research
2022
CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression
Zhang M, Liu ZZ, Aoshima K, Cai WL, Sun H, Xu T, Zhang Y, An Y, Chen JF, Chan LH, Aoshima A, Lang SM, Tang Z, Che X, Li Y, Rutter SJ, Bossuyt V, Chen X, Morrow JS, Pusztai L, Rimm DL, Yin M, Yan Q. CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Science Translational Medicine 2022, 14: eabf5473. PMID: 35108062, PMCID: PMC9003667, DOI: 10.1126/scitranslmed.abf5473.Peer-Reviewed Original ResearchConceptsBreast cancer metastasisReticuloendotheliosis viral oncogene homolog ACancer metastasisImmune suppressionM2 macrophagesWorse metastasis-free survivalMetastatic breast cancerMetastasis-free survivalV-rel avian reticuloendotheliosis viral oncogene homolog ACancer-related deathPrimary breast tumorsMultiple mouse modelsNF-κB signalingImmunocompetent settingNuclear factor-κB family membersMetastasis-promoting genesDistant metastasisMetastatic sitesPrimary tumorEffective therapyBreast cancerMetastasis treatmentMouse modelBreast tumorsMetastasis
2008
Vaccine Protection by Live, Attenuated Simian Immunodeficiency Virus in the Absence of High-Titer Antibody Responses and High-Frequency Cellular Immune Responses Measurable in the Periphery
Mansfield K, Lang S, Gauduin M, Sanford H, Lifson J, Johnson R, Desrosiers R. Vaccine Protection by Live, Attenuated Simian Immunodeficiency Virus in the Absence of High-Titer Antibody Responses and High-Frequency Cellular Immune Responses Measurable in the Periphery. Journal Of Virology 2008, 82: 4135-4148. PMID: 18272584, PMCID: PMC2292994, DOI: 10.1128/jvi.00015-08.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, ViralInterferon-gammaIntestinal MucosaLymphoid TissueMacaca mulattaNeutralization TestsRetroviridae ProteinsRNA, ViralSAIDS VaccinesSequence DeletionSimian Acquired Immunodeficiency SyndromeSimian immunodeficiency virusT-LymphocytesVaccines, AttenuatedViral Envelope ProteinsViral LoadViremiaConceptsAnti-SIV antibody responsesSimian immunodeficiency virusAntibody responseImmune responseVaccine protectionImmunodeficiency virusCopies/Gamma interferon enzyme-linked immunospotVaccine/challenge experimentsAttenuated simian immunodeficiency virusGut-associated lymphoid tissueHigh-titer antibody responsesAnti-SIV immune responsesEnzyme-linked immunospotMacrophage marker CD68Cellular immune responsesHumoral immune responseViral load measurementsWeeks of infectionNeutralization-resistant strainDouble-labeling experimentsVaccinated monkeysViral loadPeripheral bloodLymphoid tissue
2006
Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus
Kaur A, Sanford H, Garry D, Lang S, Klumpp S, Watanabe D, Bronson R, Lifson J, Rosati M, Pavlakis G, Felber B, Knipe D, Desrosiers R. Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus. Virology 2006, 357: 199-214. PMID: 16962628, PMCID: PMC1819472, DOI: 10.1016/j.virol.2006.08.007.Peer-Reviewed Original ResearchConceptsSimian immunodeficiency virusELISPOT responsesImmunodeficiency virusHSV vectorsHerpes simplex virus vectorsPlasma SIV RNAPlasma viremia levelsVector-based vaccinesDay of challengeSimplex virus vectorsNef fusion proteinRecombinant HSV vectorsSIV RNAIntravenous challengeViremia levelsAntibody titersVaccine approachesImmune responseRhesus macaquesProtective capacityMacaquesRecombinant herpesvirusDNA vectorsFusion proteinEnvInfection and Persistence of Rhesus Monkey Rhadinovirus in Immortalized B-Cell Lines
Bilello J, Lang S, Wang F, Aster J, Desrosiers R. Infection and Persistence of Rhesus Monkey Rhadinovirus in Immortalized B-Cell Lines. Journal Of Virology 2006, 80: 3644-3649. PMID: 16537632, PMCID: PMC1440374, DOI: 10.1128/jvi.80.7.3644-3649.2006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternB-LymphocytesCell Culture TechniquesCell Line, TransformedCell NucleusCell Transformation, ViralFibroblastsGenes, ReporterGenome, ViralGreen Fluorescent ProteinsHerpesviridae InfectionsHerpesvirus 4, HumanIn Situ Hybridization, FluorescenceMacaca mulattaRecombinant ProteinsRhadinovirusTime FactorsTumor Virus InfectionsVirus ReplicationA Genetic System for Rhesus Monkey Rhadinovirus: Use of Recombinant Virus To Quantitate Antibody-Mediated Neutralization
Bilello J, Morgan J, Damania B, Lang S, Desrosiers R. A Genetic System for Rhesus Monkey Rhadinovirus: Use of Recombinant Virus To Quantitate Antibody-Mediated Neutralization. Journal Of Virology 2006, 80: 1549-1562. PMID: 16415030, PMCID: PMC1346924, DOI: 10.1128/jvi.80.3.1549-1562.2006.Peer-Reviewed Original ResearchMeSH KeywordsAlkaline PhosphataseAnimalsAntibodies, ViralBase SequenceCell LineCloning, MolecularCosmidsDNA, ViralGene LibraryGenes, ReporterGenome, ViralGreen Fluorescent ProteinsHerpesviridae InfectionsHumansMacaca mulattaNeutralization TestsRecombination, GeneticRhadinovirusTumor Virus InfectionsConceptsRhesus monkey rhadinovirusGreen fluorescent proteinGenetic systemRhesus monkey fibroblastsGFP reporter geneMonkey fibroblastsGamma-2 herpesvirusKaposi's sarcoma-associated herpesvirusDifferent cell typesGenome reconstitutionSarcoma-associated herpesvirusCosmid clonesTerminal repeat regionR1 geneReporter geneRepeat regionFluorescent proteinExpression cassetteCell typesSEAP activityRRV infectivityRecombinant virusesGenomeB cellsGenes
2005
Immunization of Macaques with Single-Cycle Simian Immunodeficiency Virus (SIV) Stimulates Diverse Virus-Specific Immune Responses and Reduces Viral Loads after Challenge with SIVmac239
Evans D, Bricker J, Sanford H, Lang S, Carville A, Richardson B, Piatak M, Lifson J, Mansfield K, Desrosiers R. Immunization of Macaques with Single-Cycle Simian Immunodeficiency Virus (SIV) Stimulates Diverse Virus-Specific Immune Responses and Reduces Viral Loads after Challenge with SIVmac239. Journal Of Virology 2005, 79: 7707-7720. PMID: 15919923, PMCID: PMC1143664, DOI: 10.1128/jvi.79.12.7707-7720.2005.Peer-Reviewed Original ResearchConceptsSingle-Cycle Simian Immunodeficiency VirusesRNA copies/AIDS vaccine approachSingle-cycle SIVEnzyme-linked immunospotViral loadSimian immunodeficiency virusCopies/Immunodeficiency virusVaccine approachesGamma interferon enzyme-linked immunospotGag-specific T-cell responsesVirus-specific immune responsesMajor Histocompatibility Complex Class I DownregulationT cell proliferative responsesImmunization of macaquesPlasma viral loadT cell responsesMHC class IThird doseChronic phasePeripheral bloodWeek 8Immune responseControl animals
2004
Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus
Swigut T, Alexander L, Morgan J, Lifson J, Mansfield K, Lang S, Johnson R, Skowronski J, Desrosiers R. Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus. Journal Of Virology 2004, 78: 13335-13344. PMID: 15542684, PMCID: PMC525019, DOI: 10.1128/jvi.78.23.13335-13344.2004.Peer-Reviewed Original ResearchConceptsSimian immunodeficiency virusHuman immunodeficiency virusImmunodeficiency virusWeeks postinfectionMajor Histocompatibility Complex Class I DownregulationClass IMajor histocompatibility complex class IHistocompatibility complex class IComplex class IMHC class INef gene productParental wild-type virusImmune responseLymphocyte activationWild-type virusNef functionCD4 downregulationFunctional activityMHC downregulationDownregulationResponse-4VirusMonkeysPostinfectionNefVpx proteins of SIVmac239 and HIV-2ROD interact with the cytoskeletal protein α-actinin 1
Mueller S, Jung R, Weiler S, Lang S. Vpx proteins of SIVmac239 and HIV-2ROD interact with the cytoskeletal protein α-actinin 1. Journal Of General Virology 2004, 85: 3291-3303. PMID: 15483243, DOI: 10.1099/vir.0.80198-0.Peer-Reviewed Original ResearchMeSH KeywordsActininAmino Acid SequenceAnimalsBiological TransportChlorocebus aethiopsCOS CellsCytoplasmHIV-2Molecular Sequence DataProlineProtein Structure, TertiaryRetroviridae ProteinsSequence AlignmentSimian immunodeficiency virusTransfectionTwo-Hybrid System TechniquesViral Regulatory and Accessory ProteinsConceptsPre-integration complexNuclear localization signalNuclear importProline-rich C-terminal domainClassical import pathwayEfficient nuclear importTwo-hybrid screenAlpha-actinin 1Α-actinin 1C-terminal domainLoss of interactionImport pathwayLocalization signalCellular proteinsNuclear localizationSequence elementsCytoskeletal proteinsVpx geneVpx proteinsQuiescent cellsAA proteinViral proteinsProteinVirion particlesRed-capped mangabeys
2003
Importance of B-Cell Responses for Immunological Control of Variant Strains of Simian Immunodeficiency Virus
Johnson W, Lifson J, Lang S, Johnson R, Desrosiers R. Importance of B-Cell Responses for Immunological Control of Variant Strains of Simian Immunodeficiency Virus. Journal Of Virology 2003, 77: 375-381. PMID: 12477842, PMCID: PMC140644, DOI: 10.1128/jvi.77.1.375-381.2003.Peer-Reviewed Original ResearchConceptsHigh viral loadSimian immunodeficiency virusViral loadAntibody-mediated neutralizationImmunological controlEffective immunological controlImmunodeficiency virusVariant strainsContinuous viral replicationReplicative capacityB cell responsesGp120 envelope proteinTime of infectionHigh replicative capacityAntibody responseDisease progressionB cellsDay 14Tissue macrophagesExperimental infectionViral replicationRhesus monkeysVariable region 1InfectionV2 sequences
2002
The First HxRxG Motif in Simian Immunodeficiency Virus mac239 Vpr Is Crucial for G2/M Cell Cycle Arrest
Mueller S, Lang S. The First HxRxG Motif in Simian Immunodeficiency Virus mac239 Vpr Is Crucial for G2/M Cell Cycle Arrest. Journal Of Virology 2002, 76: 11704-11709. PMID: 12388729, PMCID: PMC136740, DOI: 10.1128/jvi.76.22.11704-11709.2002.Peer-Reviewed Original ResearchConceptsCell cycle arrestCell cycle arrest functionCycle arrestArrest functionVpr mutantsAlpha-helical domainAlpha-helical regionG2/M cell cycle arrestLong terminal repeatM cell cycle arrestNuclear importArrest of cellsSIV long terminal repeatTranscriptional transactivationPreintegration complexSecond motifFunctional domainsReduced transactivationVpr proteinTerminal repeatAmino acidsTransactivationSingle substitutionMotifMutantsKaposi's sarcoma associated herpesvirus immune evasion strategies.
Means R, Lang S, Chung Y, Jung J. Kaposi's sarcoma associated herpesvirus immune evasion strategies. Frontiers In Bioscience-Landmark 2002, 7: e185-203. PMID: 11991843, DOI: 10.2741/a915.Peer-Reviewed Original Research
2000
Simian Immunodeficiency Virus Containing Mutations in N-Terminal Tyrosine Residues and in the PxxP Motif in Nef Replicates Efficiently in Rhesus Macaques
Carl S, Iafrate A, Lang S, Stolte N, Stahl-Hennig C, Mätz-Rensing K, Fuchs D, Skowronski J, Kirchhoff F. Simian Immunodeficiency Virus Containing Mutations in N-Terminal Tyrosine Residues and in the PxxP Motif in Nef Replicates Efficiently in Rhesus Macaques. Journal Of Virology 2000, 74: 4155-4164. PMID: 10756028, PMCID: PMC111930, DOI: 10.1128/jvi.74.9.4155-4164.2000.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCD4 AntigensCell Line, TransformedCOS CellsDown-RegulationGene Products, nefHistocompatibility Antigens Class IHumansMacaca mulattaMutagenesisP21-Activated KinasesPhosphorylationProtein Serine-Threonine KinasesSimian immunodeficiency virusSrc Homology DomainsTyrosineViral LoadVirus ReplicationConceptsAbility of NefTyrosine-based endocytosis signalTyrosine residuesHigh viral loadCellular signal transductionTyrosine kinase SrcNef functionViral loadEndocytosis signalEndocytic machineryPXXP motifN-terminal tyrosine residueCell surface expressionKinase SrcKinase assaysSignal transductionProline residuesClass I major histocompatibility complexN-terminal tyrosineI major histocompatibility complexLigand domainCombined mutationsNef interactionsMajor histocompatibility complexMutations
1999
The Acidic Region and Conserved Putative Protein Kinase C Phosphorylation Site in Nef Are Important for SIV Replication in Rhesus Macaques
Carl S, Iafrate A, Lang S, Stahl-Hennig C, Kuhn E, Fuchs D, Mätz-Rensing K, Haaft P, Heeney J, Skowronski J, Kirchhoff F. The Acidic Region and Conserved Putative Protein Kinase C Phosphorylation Site in Nef Are Important for SIV Replication in Rhesus Macaques. Virology 1999, 257: 138-155. PMID: 10208928, DOI: 10.1006/viro.1999.9645.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCD4 AntigensCOS CellsGene Products, nefHistocompatibility Antigens Class IHIV-1Hydrogen-Ion ConcentrationMacaca mulattaMolecular Sequence DataMutagenesis, Site-DirectedNef Gene Products, Human Immunodeficiency VirusPhosphorylationProtein Kinase CSimian immunodeficiency virusSurface PropertiesVirus ReplicationConceptsProtein kinase C phosphorylation sitesKinase C phosphorylation sitesC phosphorylation sitesPhosphorylation sitesPutative protein kinase C phosphorylation sitePotential protein kinase C phosphorylation sitesAcidic regionWild-type activityPKC phosphorylation sitesJurkat T cellsSignal transductionAbility of NefReplication assaysFunctional relevanceCell culture systemMutant virusNef functionPathogenic SIVmac239 cloneAcidic chargeReduced infectivityReplicationCulture systemNefRapid reversionRhesus macaques
1997
Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques
Lang S, Lafrate A, Stahl-Hennig C, Kuhn E, Nisslein T, Kaup F, Haupt M, Hunsmann G, Skowronski J, Kirchhoff F. Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques. Nature Medicine 1997, 3: 860-865. PMID: 9256276, DOI: 10.1038/nm0897-860.Peer-Reviewed Original ResearchConceptsCellular serine/threonine kinaseSerine/threonine kinaseThreonine kinaseTyrosine kinase SrcPutative SH3Simian immunodeficiency virus NefKinase SrcMutant formsEfficient replicationKinaseInduction of AIDSSimian immunodeficiency virusNef geneCD4 downregulationSIVmac NefRhesus macaquesRapid deathNef sequencesSH3NefSrcGenesDomainDifferent time pointsPathogenicity
1995
Identification of Lck-binding Elements in Tip of Herpesvirus Saimiri (∗)
Jung J, Lang S, Friedrich U, Jun T, Roberts T, Desrosiers R, Biesinger B. Identification of Lck-binding Elements in Tip of Herpesvirus Saimiri (∗). Journal Of Biological Chemistry 1995, 270: 20660-20667. PMID: 7544793, DOI: 10.1074/jbc.270.35.20660.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceBinding SitesCell LineChlorocebus aethiopsDNA PrimersHerpesvirus 2, SaimiriineLymphocyte Specific Protein Tyrosine Kinase p56(lck)Molecular Sequence DataMutagenesis, Site-DirectedPeptide FragmentsPhosphoproteinsPhosphoserinePhosphothreoninePhosphotyrosinePoint MutationPolymerase Chain ReactionProtein-Tyrosine KinasesRatsRecombinant ProteinsSequence Homology, Amino AcidSpodopteraStructure-Activity RelationshipTransfectionTyrosineViral ProteinsConceptsC-terminal SrcCellular protein kinasesBinding of sequencesInteraction of TipHerpesvirus saimiriLck kinase activityCOS-1 cellsRat-1 cell lineLck functionPutative SH3Cellular proteinsSH3 bindingProtein kinaseCarboxyl terminusLck kinaseVivo associationKinase activityMutational analysisFusion proteinLckAmino acidsKinaseHuman T cellsProteinCell linesIdentification of a nef allele that causes lymphocyte activation and acute disease in Macaque monkeys
Du Z, Lang S, Sasseville V, Lackner A, Ilyinskii P, Daniel M, Jung J, Desrosiers R. Identification of a nef allele that causes lymphocyte activation and acute disease in Macaque monkeys. Cell 1995, 82: 665-674. PMID: 7664345, DOI: 10.1016/0092-8674(95)90038-1.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAllelesAmino Acid SequenceAnimalsBase SequenceDNA PrimersDNA, ViralGene Products, envGene Products, nefGenes, nefLymphocyte ActivationMacaca mulattaMiceMolecular Sequence DataPhagocytesPhenotypePhosphorylationRetroviridae Proteins, OncogenicSignal TransductionSimian Acquired Immunodeficiency SyndromeSimian immunodeficiency virusTransformation, GeneticTyrosineViral Fusion ProteinsVirus ReplicationConceptsAcute diseasePeripheral blood mononuclear cell culturesBlood mononuclear cell culturesMononuclear cell culturesT lymphocyte activationSevere diarrheaLymphoid proliferationsGastrointestinal tractNef allelesMacaque monkeysLymphocyte activationCellular activationSIVmac239NefDiseaseActivationMonkeysCell culturesImportant determinantCellsNIH 3T3 cellsTyrosine phosphorylationCotransfected COS cellsCOS cellsDiarrheavpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys
Hoch J, Lang S, Weeger M, Stahl-Hennig C, Coulibaly C, Dittmer U, Hunsmann G, Fuchs D, Müller J, Sopper S. vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys. Journal Of Virology 1995, 69: 4807-4813. PMID: 7609047, PMCID: PMC189293, DOI: 10.1128/jvi.69.8.4807-4813.1995.Peer-Reviewed Original ResearchProgression to AIDS in the absence of a gene for vpr or vpx
Gibbs J, Lackner A, Lang S, Simon M, Sehgal P, Daniel M, Desrosiers R. Progression to AIDS in the absence of a gene for vpr or vpx. Journal Of Virology 1995, 69: 2378-2383. PMID: 7884883, PMCID: PMC188910, DOI: 10.1128/jvi.69.4.2378-2383.1995.Peer-Reviewed Original ResearchConceptsLow virus burdenSimian immunodeficiency virusVirus burdenRhesus monkeysLymphocyte concentrationsPlasma antigenemiaHigh virus burdenLymph node morphologyImmunodeficiency virusDisease progressionSIVmac replicationPrimate lentivirusesVirus replicationWild-type virusNode morphologyAIDSVpx geneTerminal stageProgressionAntigenemiaCD4VpxMonkeysEarly spikeBurden