Chimeric HIV-1 Envelope Glycoproteins with Potent Intrinsic Granulocyte-Macrophage Colony-Stimulating Factor GM-CSF) Activity.docVIP

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Chimeric HIV-1 Envelope Glycoproteins with Potent Intrinsic Granulocyte-Macrophage Colony-Stimulating Factor GM-CSF) Activity.doc

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Chimeric HIV-1 Envelope Glycoproteins with Potent Intrinsic Granulocyte-Macrophage Colony-Stimulating Factor GM-CSF) Activity

ChimericHIV-1EnvelopeGlycoproteinswithPotent IntrinsicGranulocyte-MacrophageColony-Stimulating Factor(GM-CSF)Activity* Go¨zdeIsik1.,ThijsvanMontfort1.,MaikelBoot1,VivianaCobosJime′nez2,NeeltjeA.Kootstra2, RogierW.Sanders1,3 * 1Department of Medical Microbiology, Laboratory of Experimental Virology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2Department of Experimental Immunology, Sanquin Research, Landsteiner Laboratory, Center for Infection and Immunity Amsterdam,AcademicMedicalCenter,UniversityofAmsterdam,Amsterdam,TheNetherlands,3DepartmentofMicrobiologyandImmunology,WeillMedicalCollegeof CornellUniversity,NewYork,UnitedStatesofAmerica Abstract HIV-1 acquisition can be prevented by broadly neutralizing antibodies (BrNAbs) that target the envelope glycoprotein complex(Env).AnidealvaccineshouldthereforebeabletoinduceBrNAbsthatcanprovideimmunityoveraprolonged periodoftime,butthelowintrinsicimmunogenicityofHIV-1EnvmakestheelicitationofsuchBrNAbschallenging.Co- stimulatorymoleculescanincreasetheimmunogenicityofEnvandwehaveengineeredasolublechimericEnvtrimerwith an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain. This chimeric molecule induced enhancedBandhelperTcellresponsesinmicecomparedtoEnvwithoutGM-CSF.Westudiedwhetherwecouldoptimize theactivityoftheembeddedGM-CSFaswellastheantigenicstructureoftheEnvcomponentofthechimericmolecule.We assessedtheeffectoftruncatingGM-CSF,removingglycosylation-sitesinGM-CSF,andadjustingthelinkerlengthbetween GM-CSF and Env. One of our designed EnvGM-CSF chimeras improved GM-CSF-dependent cell proliferation by 6-fold, reachingthesameactivityassolublerecombinantGM-CSF.Inaddition,weincorporatedGM-CSFintoacleavableEnvtrimer andfoundthatinsertionofGM-CSFdidnotcompromiseEnvcleavage,whileEnvcleavagedidnotcompromiseGM-CSF activity. Importantly, these optimized EnvGM-CSF proteins were able to differentiate human monocytes into cells with