Measles Virus Glycoprotein-Based Lentiviral Targeting Vectors That Avoid Neutralizing Antibodies 英文参考文献.docVIP

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Measles Virus Glycoprotein-Based Lentiviral Targeting Vectors That Avoid Neutralizing Antibodies 英文参考文献.doc

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Measles Virus Glycoprotein-Based Lentiviral Targeting Vectors That Avoid Neutralizing Antibodies 英文参考文献

MeaslesVirusGlycoprotein-BasedLentiviralTargeting VectorsThatAvoidNeutralizingAntibodies SabrinaKneissl1*,TobiasAbel1,AnkeRasbach1,JuliaBrynza1,Ju¨rgenSchneider-Schaulies2, ChristianJ.Buchholz1* 1Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany, 2Institute of Virology and Immunobiology, University of Wu¨rzburg, Wu¨rzburg, Germany Abstract Lentiviralvectors(LVs)arepotentgenetransfervehiclesfrequentlyappliedinresearchandrecentlyalsoinclinicaltrials. RetargetingLVentrytocelltypesofinterestisakeyissuetoimprovegenetransfersafetyandefficacy.Recently,wehave developedatargetingmethodforLVsbyincorporatingengineeredmeaslesvirus(MV)glycoproteins,thehemagglutinin (H),responsibleforreceptorrecognition,andthefusionproteinintotheirenvelope.TheHproteindisplaysasingle-chain antibody(scFv)specificforthetargetreceptorandisablatedforrecognitionoftheMVreceptorsCD46andSLAMbypoint mutations in its ectodomain. A potential hindrance to systemic administration in humans is pre-existing MV-specific immunityduetovaccinationornaturalinfection.Wecomparedtransductionoftargetingvectorsandnon-targetingvectors pseudotyped with MV glycoproteins unmodified in their ectodomains (MV-LV) in presence of a-MV antibody-positive human plasma. At plasma dilution 1:160 MV-LV was almost completely neutralized, whereas targeting vectors showed relative transduction efficiencies from 60% to 90%. Furthermore, at plasma dilution 1:80 an at least 4-times higher multiplicity of infection (MOI) of MV-LV had to be applied to obtain similar transduction efficiencies as with targeting vectors.Alsowhenthevectorswerenormalizedtotheirp24values,targetingvectorsshowedpartialprotectionagainsta- MVantibodiesinhumanplasma.Furthermore,themonoclonalneutralizingantibodyK71withaputativeepitopecloseto thereceptorbindingsitesofH,didnotneutralizethetargetingvectors,butdidneutralizeMV-LV.Theobservedescapefrom neutralizationmaybeduetothepointmutationsintheHectodomainthatmighthavedestroyedantibodybindings