2013
Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection
Didigu CA, Wilen CB, Wang J, Duong J, Secreto AJ, Danet-Desnoyers GA, Riley JL, Gregory PD, June CH, Holmes MC, Doms RW. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood 2013, 123: 61-69. PMID: 24162716, PMCID: PMC3879906, DOI: 10.1182/blood-2013-08-521229.Peer-Reviewed Original ResearchConceptsC chemokine receptor 5HIV-1 infectionT cellsHIV-1HIV coreceptor CCR5Chemokine receptor 5Humanized mouse modelDrug-free treatmentHIV-1 entryHIV coreceptorsPharmacologic blockadeCoreceptor CCR5Mouse modelCells engraftReceptor 5Gene-modified cellsCXCR4InfectionPrimary humanCoreceptorCD4CCR5Genetic inactivationVirusCells
2012
Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5
Parker ZF, Iyer SS, Wilen CB, Parrish NF, Chikere KC, Lee FH, Didigu CA, Berro R, Klasse PJ, Lee B, Moore JP, Shaw GM, Hahn BH, Doms RW. Transmitted/Founder and Chronic HIV-1 Envelope Proteins Are Distinguished by Differential Utilization of CCR5. Journal Of Virology 2012, 87: 2401-2411. PMID: 23269796, PMCID: PMC3571396, DOI: 10.1128/jvi.02964-12.Peer-Reviewed Original ResearchConceptsCCR5 expression levelsF EnvsTransmitted/FounderHIV-1 envelope proteinCCR5 antagonist maravirocSingle genome amplificationExpression levelsSingle virus variantReplication-competent virusMVC resistanceFounder virusesChronic infectionCCR5 antagonistsT cellsHIV-1CCR5MaravirocControl virusPhysiologic levelsCCR5 conformationsVirus variantsEnvelope glycoproteinEnv proteinEnvInfectionTransmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7
Parrish NF, Wilen CB, Banks LB, Iyer SS, Pfaff JM, Salazar-Gonzalez JF, Salazar MG, Decker JM, Parrish EH, Berg A, Hopper J, Hora B, Kumar A, Mahlokozera T, Yuan S, Coleman C, Vermeulen M, Ding H, Ochsenbauer C, Tilton JC, Permar SR, Kappes JC, Betts MR, Busch MP, Gao F, Montefiori D, Haynes BF, Shaw GM, Hahn BH, Doms RW. Transmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7. PLOS Pathogens 2012, 8: e1002686. PMID: 22693444, PMCID: PMC3364951, DOI: 10.1371/journal.ppat.1002686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, NeutralizingAntibodies, ViralCD4 AntigensCD4-Positive T-LymphocytesCells, CulturedCloning, MolecularHIV Envelope Protein gp120HIV InfectionsHIV-1Host-Pathogen InteractionsHumansIntegrinsMucous MembraneNeutralization TestsReceptors, CCR5Viral TropismVirus InternalizationVirus ReplicationConceptsF virusesInfectious molecular cloneMucosal HIV-1 acquisitionNew HIV-1 infectionsHuman immunodeficiency virus type 1Immunodeficiency virus type 1Transmitted/FounderHIV-1 acquisitionHIV-1 vaccine designSubtype C HIVHIV-1 infectionSingle genome amplificationAnti-α4β7 antibodyVirus type 1V2 variable loopsChronic EnvsC HIVFounder virusesSexual transmissionChronic virusesGp120 subunitIntegrin α4β7Transmission fitnessSame CD4CD4HIV: Cell Binding and Entry
Wilen CB, Tilton JC, Doms RW. HIV: Cell Binding and Entry. Cold Spring Harbor Perspectives In Medicine 2012, 2: a006866. PMID: 22908191, PMCID: PMC3405824, DOI: 10.1101/cshperspect.a006866.Peer-Reviewed Original ResearchConceptsHIV entryViral tropismPrimary cellular receptor CD4Human immunodeficiency virus (HIV) replicationAbility of HIVImmunodeficiency virus replicationHost immune responseHuman immune systemCellular receptor CD4Immune responseCellular coreceptorTherapeutic interventionsImmune systemReceptor CD4Virus replicationHIVCell bindingHost cell cytoplasmTropismHost cell membraneTrigger fusionCell cytoplasmCD4Major rolePathogenesis
2011
Molecular Mechanisms of HIV Entry
Wilen CB, Tilton JC, Doms RW. Molecular Mechanisms of HIV Entry. Advances In Experimental Medicine And Biology 2011, 726: 223-242. PMID: 22297516, DOI: 10.1007/978-1-4614-0980-9_10.Peer-Reviewed Original ResearchConceptsHIV entryOnly viral surface proteinHuman immunodeficiency virus (HIV) entryHumoral immune responseMembrane fusion machineryCoreceptor-binding siteHost protein CD4Viral surface proteinsHIV infectionSmall molecule inhibitorsImmune responseChemokine coreceptorsFusion machineryViral tropismClinical treatmentVirus entryMolecular mechanismsHost cellsFacilitates exposureMolecule inhibitorsGp41 subunitSurface proteinsViral genomeAmino acidsCD4Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases
Wilen CB, Wang J, Tilton JC, Miller JC, Kim KA, Rebar EJ, Sherrill-Mix SA, Patro SC, Secreto AJ, Jordan AP, Lee G, Kahn J, Aye PP, Bunnell BA, Lackner AA, Hoxie JA, Danet-Desnoyers GA, Bushman FD, Riley JL, Gregory PD, June CH, Holmes MC, Doms RW. Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases. PLOS Pathogens 2011, 7: e1002020. PMID: 21533216, PMCID: PMC3077364, DOI: 10.1371/journal.ppat.1002020.Peer-Reviewed Original ResearchConceptsT cellsHIV-1Human CD4X4-tropic HIV-1X4 HIV-1CCR5-tropic virusHumanized mouse modelLoss of CXCR4CXCR4-tropic HIVHIV-1 entryHuman T cellsCCR5Δ32 polymorphismAdoptive transferAutologous transplantCell surface expressionCXCR4 coreceptorMouse modelCD4CCR5CXCR4Surface expressionHIVInfectionSuch cellsHost cells
2010
A Maraviroc-Resistant HIV-1 with Narrow Cross-Resistance to Other CCR5 Antagonists Depends on both N-Terminal and Extracellular Loop Domains of Drug-Bound CCR5
Tilton JC, Wilen CB, Didigu CA, Sinha R, Harrison JE, Agrawal-Gamse C, Henning EA, Bushman FD, Martin JN, Deeks SG, Doms RW. A Maraviroc-Resistant HIV-1 with Narrow Cross-Resistance to Other CCR5 Antagonists Depends on both N-Terminal and Extracellular Loop Domains of Drug-Bound CCR5. Journal Of Virology 2010, 84: 10863-10876. PMID: 20702642, PMCID: PMC2950574, DOI: 10.1128/jvi.01109-10.Peer-Reviewed Original ResearchMeSH KeywordsBase SequenceBinding SitesCCR5 Receptor AntagonistsCell LineCohort StudiesCyclohexanesDNA PrimersDrug Resistance, ViralHIV Envelope Protein gp120HIV Fusion InhibitorsHIV InfectionsHIV-1HumansIn Vitro TechniquesMaravirocModels, BiologicalMutant ProteinsMutationPeptide FragmentsProtein Structure, TertiaryReceptors, CCR5TriazolesConceptsCCR5 antagonistsLow CCR5 levelsTreatment-experienced patientsPlasma viral RNACCR5 antagonist maravirocCourse of treatmentHigh-level resistanceMVC resistanceMVC treatmentVirologic failureExtracellular loopCCR5 levelsTreatment regimensCross-resistance profilesCXCR4 useV3 loopCCR5 useHIV entryHIV-1Viral envelope proteinsCCR5V4 loopsAntagonistMaravirocPatientsHIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4+ T Cells
Pfaff JM, Wilen CB, Harrison JE, Demarest JF, Lee B, Doms RW, Tilton JC. HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4+ T Cells. Journal Of Virology 2010, 84: 6505-6514. PMID: 20410277, PMCID: PMC2903254, DOI: 10.1128/jvi.00374-10.Peer-Reviewed Original ResearchConceptsT cellsResistant virusesAntagonist aplavirocCCR5 antagonistsTropism shiftSmall-molecule CCR5 antagonistsEffector memory cellsT cell subsetsHIV-1 resistanceT cell homeostasisVirologic failureCell subsetsV3 loopPrimary CD4Virus infectionRelative sparingHost determinantsImmune functionCCR5Heterologous virusesViral resistanceViral tropismCentral memoryDrug resistanceAltered tropism