I. George Miller Jr, MD
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John F. Enders Professor of Pediatrics (Infectious Disease) and Professor of Epidemiology (Microbial Diseases) and of Molecular Biophysics and Biochemistry
Biography
Dr. Miller’s laboratory studies the mechanisms underlying the switch between latency and lytic replication of two oncogenic herpesviruses, Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus. Current experiments explore how viral and cellular transcription factors that selectively bind to methylated DNA control expression of viral and cellular genes, how cellular gene expression is selectively inhibited while viral gene expression is enhanced, and how viral DNA replication is regulated by cellular proteins. Recent studies focus on a new class of anti-viral agents that inhibit reactivation of Epstein-Barr virus from latency into lytic infection.
Appointments
Pediatric Infectious Diseases
ProfessorPrimaryMolecular Biophysics and Biochemistry
ProfessorSecondaryEpidemiology of Microbial Diseases
ProfessorSecondary
Other Departments & Organizations
- Biochemistry, Quantitative Biology, Biophysics and Structural Biology (BQBS)
- Epidemiology of Microbial Diseases
- Genomics, Genetics, and Epigenetics
- Microbiology
- Molecular Biophysics and Biochemistry
- Molecular Virology
- Pediatric Infectious Diseases
- Pediatric Infectious Diseases Consultation Program
- Pediatrics
- Virology Laboratories
- Yale Cancer Center
- Yale Combined Program in the Biological and Biomedical Sciences (BBS)
- Yale School of Public Health
- Yale Ventures
- Yale-UPR Integrated HIV Basic and Clinical Sciences Initiative
Education & Training
- Research Fellow
- Children's Hospital, Boston (1969)
- Research Fellow
- Harvard Medical School (1969)
- Fellow
- CDC (1966)
- Intern & Assistant Resident
- University Hospital, Cleveland (1964)
- MD
- Harvard Medical School (1962)
- AB
- Harvard College (1958)
Board Certifications
Internal Medicine
- Certification Organization
- AB of Internal Medicine
- Original Certification Date
- 1972
Research
Overview
We study two related human tumor viruses: Epstein-Barr virus (EBV), which is associated with lymphomas and carcinomas; and Kaposi’s sarcoma-associated herpesvirus (KSHV), which is associated with Kaposi’s sarcoma and lymphomas that occur in patients with AIDS. Both viruses establish “latent states” in host cells, during which only a limited number of viral genes are expressed. We have discovered multifunctional virally encoded transcription factors and replication proteins, ZEBRA and Rta in EBV and KSHV ORF50, which mediate a switch between latency and the lytic cycle. Our lab studies the control of ZEBRA, Rta and ORF50 expression and their mechanisms of action and interaction. We are interested in the basis of viral specificity of these activators. We also investigate how the immune system detects and regulates the latent and lytic cycle program of EBV in B cells.
Medical Subject Headings (MeSH)
Biophysics; Epstein-Barr Virus Infections; Infectious Disease Medicine; Pediatrics; Sarcoma, Kaposi; Virology
Research at a Glance
Yale Co-Authors
Frequent collaborators of I. George Miller's published research.
Publications Timeline
A big-picture view of I. George Miller's research output by year.
Research Interests
Research topics I. George Miller is interested in exploring.
Lee Heston
Eugene Shapiro, MD
Joseph Craft, MD
Kaveh Khoshnood, PhD, MPH
88Publications
7,496Citations
Sarcoma, Kaposi
Epstein-Barr Virus Infections
Publications
2019
Cellular Genes Involved in Redox Regulation Are Altered by Inhibitors of Epstein‐Barr Virus Lytic Gene Expression
Gorres K, Miller G. Cellular Genes Involved in Redox Regulation Are Altered by Inhibitors of Epstein‐Barr Virus Lytic Gene Expression. The FASEB Journal 2019, 33: 458.11-458.11. DOI: 10.1096/fasebj.2019.33.1_supplement.458.11.Peer-Reviewed Original ResearchConceptsViral lytic gene expressionLytic gene expressionCellular genesGene expressionViral lytic cycleLytic cycleEpstein-Barr virusNext-generation RNA sequencingViral immediate-early genesCellular gene expressionImmediate early genesRedox regulationTranscription factorsRNA sequencingCellular pathwaysGenesEnvironmental stimuliHuman cancersRedox statusMore virionsEBV-positive cellsFASEB JournalFull-text articlesExpressionViral lytic cascade
2008
Regulation of Expression, Mode of Action and Downstream Targets of ORF50 Protein in KSHV Lytic Cycle Activation
Chang P, Ye J, Miller G. Regulation of Expression, Mode of Action and Downstream Targets of ORF50 Protein in KSHV Lytic Cycle Activation. 2008, 521-553. DOI: 10.1007/978-0-387-68945-6_21.Peer-Reviewed Original ResearchCitationsConceptsKaposi's sarcoma-associated herpesvirusSarcoma-associated herpesvirusLytic cycle activationMulticentric Castleman's diseaseHuman herpesvirus 8Primary effusion lymphomaHIV/AIDSORF50 proteinCastleman's diseaseViral lytic replication cycleLytic replication cycleKaposi's sarcomaHerpesvirus 8Viral life cycleEffusion lymphomaViral gene productsHuman malignanciesViral targetsKSHV pathogenesisLytic replicationMode of action
2001
Autostimulation of the Epstein-Barr Virus BRLF1 Promoter Is Mediated through Consensus Sp1 and Sp3 Binding Sites
Ragoczy T, Miller G. Autostimulation of the Epstein-Barr Virus BRLF1 Promoter Is Mediated through Consensus Sp1 and Sp3 Binding Sites. Journal Of Virology 2001, 75: 5240-5251. PMID: 11333906, PMCID: PMC114930, DOI: 10.1128/jvi.75.11.5240-5251.2001.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsBase SequenceBinding SitesB-LymphocytesCell Line, TransformedDNA-Binding ProteinsGene DeletionGene Expression Regulation, ViralHerpesvirus 4, HumanHeterotrimeric GTP-Binding ProteinsHumansImmediate-Early ProteinsMolecular Sequence DataMutagenesis, Site-DirectedPromoter Regions, GeneticProtein BindingReceptors, Cell SurfaceSp1 Transcription FactorSp3 Transcription FactorTrans-ActivatorsTranscription FactorsViral ProteinsVirus ActivationConceptsSp1/Sp3 siteLytic cycleSp3 transcription factorsBinding of Sp1Transcriptional start siteSite-directed mutagenesisGel shift analysisBRLF1 promoterReporter-based assaysEpstein–Barr virus Rta proteinCellular Sp1Own geneConsensus Sp1Transcriptional activationCellular proteinsTranscription factorsStart siteDNA bindingOwn expressionMutagenesis studiesRta proteinSp1Reporter activityTranscription factor Zif268B cellsCD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation
Nikiforow S, Bottomly K, Miller G. CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation. Journal Of Virology 2001, 75: 3740-3752. PMID: 11264363, PMCID: PMC114865, DOI: 10.1128/jvi.75.8.3740-3752.2001.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAdultB-LymphocytesCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell DivisionCell SizeCells, CulturedEpstein-Barr Virus InfectionsEpstein-Barr Virus Nuclear AntigensFlow CytometryHerpesvirus 4, HumanHumansImmunologic MemoryLymphocyte CountReceptors, IgESerologyTacrolimusT-Lymphocyte SubsetsConceptsEpstein-Barr virusB cell proliferationT cellsB cellsB-cell lymphoproliferative diseaseRemoval of CD4Effector T cellsMemory T cellsT cell effectorsT cell surveillanceCytolytic T cellsEarly proliferative phaseCell linesImmune controlLymphoproliferative diseaseImmunodeficient hostsImmune surveillanceLymphoblastoid cell linesCD4Proliferative phaseImmortalized cell linesCD8CD23VirusInfectionPREVALENCE OF ANTIBODIES TO HUMAN HERPESVIRUS 8 (HHV-8) IN SAUDI ARABIAN PATIENTS WITH AND WITHOUT RENAL FAILURE1234
Almuneef M, Nimjee S, Khoshnood K, Miller G, Rigsby M. PREVALENCE OF ANTIBODIES TO HUMAN HERPESVIRUS 8 (HHV-8) IN SAUDI ARABIAN PATIENTS WITH AND WITHOUT RENAL FAILURE1234. Transplantation 2001, 71: 1120-1124. PMID: 11374413, DOI: 10.1097/00007890-200104270-00019.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsEnd-stage renal diseasePosttransplantation Kaposi's sarcomaPrevalence of antibodiesKaposi's sarcomaHuman herpesvirus 8HHV-8Renal diseaseHerpesvirus 8High incidenceHHV-8-seropositive individualsSmall viral capsid antigenHHV-8 infectionRenal transplant recipientsViral capsid antigenComparison groupArea of residenceSeronegative subjectsESRD patientsSeropositive subjectsTransplant recipientsCapsid antigenSerologic evidenceSeropositive individualsCommon cancerPatients
2000
Kaposi's Sarcoma-Associated Herpesvirus Open Reading Frame 50/Rta Protein Activates the Entire Viral Lytic Cycle in the HH-B2 Primary Effusion Lymphoma Cell Line †
Gradoville L, Gerlach J, Grogan E, Shedd D, Nikiforow S, Metroka C, Miller G. Kaposi's Sarcoma-Associated Herpesvirus Open Reading Frame 50/Rta Protein Activates the Entire Viral Lytic Cycle in the HH-B2 Primary Effusion Lymphoma Cell Line †. Journal Of Virology 2000, 74: 6207-6212. PMID: 10846108, PMCID: PMC112123, DOI: 10.1128/jvi.74.13.6207-6212.2000.Peer-Reviewed Original ResearchCitationsAltmetricGenetically and epidemiologically related “non‐syncytium‐inducing” isolates of HIV‐1 display heterogeneous growth patterns in macrophages
Jesus M, Anders C, Miller G, Sleasman J, Goodenow M, Andiman W. Genetically and epidemiologically related “non‐syncytium‐inducing” isolates of HIV‐1 display heterogeneous growth patterns in macrophages. Journal Of Medical Virology 2000, 61: 171-180. PMID: 10797371, DOI: 10.1002/(sici)1096-9071(200006)61:2<171::aid-jmv1>3.0.co;2-x.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsMeSH KeywordsAdultAmino Acid SequenceAntigens, ViralCD4 AntigensCell LineCells, CulturedChild, PreschoolFemaleGiant CellsHIV Core Protein p24HIV InfectionsHIV-1HumansInfantLeukocytes, MononuclearMacrophagesMolecular Sequence DataPhenotypeProspective StudiesProtein Structure, TertiaryReceptors, ChemokineTransfectionTropismU937 CellsViral ProteinsVirus ReplicationConceptsNSI virusesDisease stageSurrogate markerPediatric human immunodeficiency virus type 1 (HIV-1) infectionHuman immunodeficiency virus type 1 (HIV-1) infectionVirus type 1 infectionCell linesCo-receptor preferenceM-tropic virusesType 1 infectionT-cell tropicDual tropicInducing (NSI) virusesNSI isolatesAsymptomatic childrenMacrophage-tropicClinical progressionSymptomatic childrenV3 loopNSI phenotypeHIV-1Lymphotropic virusCategory A1Heterogeneous growth patternsGenetic featuresDihydrofolate Reductase from Kaposi's Sarcoma-Associated Herpesvirus
Cinquina C, Grogan E, Sun R, Lin S, Beardsley G, Miller G. Dihydrofolate Reductase from Kaposi's Sarcoma-Associated Herpesvirus. Virology 2000, 268: 201-217. PMID: 10683342, DOI: 10.1006/viro.1999.0165.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsKaposi's sarcoma-associated herpesvirusSarcoma-associated herpesvirusDihydrofolate reductaseEarly lytic cycle genesNucleotide metabolism genesDHFR activityHuman DHFRViral enzymesPrimary effusion lymphomaLytic cycle genesKSHV lytic cycleMethionine biosynthesisCycle genesHuman dihydrofolate reductaseCultured B-cell linesMetabolism genesPEL cell linesOwn enzymesB cell linesAmino acidsPEL cellsChemical inductionLytic cycleE. coliInfected cells
1999
Role of the epstein-barr virus RTA protein in activation of distinct classes of viral lytic cycle genes.
Ragoczy T, Miller G. Role of the epstein-barr virus RTA protein in activation of distinct classes of viral lytic cycle genes. Journal Of Virology 1999, 73: 9858-66. PMID: 10559298, PMCID: PMC113035, DOI: 10.1128/jvi.73.12.9858-9866.1999.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsLytic cycle genesRaji cellsEpstein–Barr virus Rta proteinEpstein-Barr virus (EBV) lytic cycleViral targetsLytic cycleVirus lytic cycleLymphoma cell line RajiBurkitt's lymphoma cell line RajiBZLF1 expressionB cell linesCell line RajiBRLF1 geneImmediate early genesInhibitory effectCycle genesViral lytic cycle genesEBVRta proteinViral genesBLRF2CellsExpressionTransactivation functionLate genesAmino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator.
Francis A, Ragoczy T, Gradoville L, Heston L, El-Guindy A, Endo Y, Miller G. Amino acid substitutions reveal distinct functions of serine 186 of the ZEBRA protein in activation of early lytic cycle genes and synergy with the Epstein-Barr virus R transactivator. Journal Of Virology 1999, 73: 4543-51. PMID: 10233912, PMCID: PMC112494, DOI: 10.1128/jvi.73.6.4543-4551.1999.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsLytic cycle genesLatent virusZEBRA proteinOverexpression of RtaEpstein-Barr virusLatent EBV genomeBRLF1 expressionEarly lytic cycle genesAmino acid substitutionsEBV genomeBRLF1BRLF1 promoterCycle genesAcid substitutionsVirusEpstein-Barr virus R transactivatorSerine 186Distinct phenotypesLytic life cycleR transactivatorActivationDifferent amino acid substitutionsResponse elementS186Expression
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- May 11, 2022
Viruses and Cancer: How a 45-year Legacy of Collaboration Led to Discoveries about Epstein-Barr, SV40
- April 05, 2022
100 Years of Pediatrics at Yale
- April 01, 2020Source: Washington Post
Opinion: We need a new test to know who has had — and recovered from — the coronavirus
- September 24, 2019
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