Anti-HIV-1 Activity of Elafin Depends on Its Nuclear Localization and Altered Innate Immune Activation in Female Genital Epithelial Cells.docVIP

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Anti-HIV-1 Activity of Elafin Depends on Its Nuclear Localization and Altered Innate Immune Activation in Female Genital Epithelial Cells.doc

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Anti-HIV-1 Activity of Elafin Depends on Its Nuclear Localization and Altered Innate Immune Activation in Female Genital Epithelial Cells

Anti-HIV-1ActivityofElafinDependsonItsNuclear LocalizationandAlteredInnateImmuneActivationin FemaleGenitalEpithelialCells AnnaG.Drannik1.,KakonNag1.,Xiao-DanYao1,BethanyM.Henrick1,T.BlakeBall2, FrancisA.Plummer2,CharlesWachihi3,JoshuaKimani3,KennethL.Rosenthal1* 1DepartmentofPathologyandMolecularMedicine,McMasterImmunologyResearchCentre,MichaelG.DeGrooteInstituteforInfectiousDiseaseResearch,McMaster University,Hamilton,Ontario,Canada,2DepartmentofMedicalMicrobiology,UniversityofManitobaandPublicHealthAgencyofCanada,Winnipeg,Manitoba,Canada, 3DepartmentofMedicalMicrobiology,UniversityofNairobi,Nairobi,Kenya Abstract Elafin(E)anditsprecursortrappin-2(Tr)arealarmantiproteaseswithantimicrobialandimmunomodulatoryactivities.Trand E (Tr/E) have been associated with HIV-1 resistance. We recently showed that Tr/E reduced IL-8 secretion and NF-kB activationinresponsetoamimicofviraldsRNAandcontributedtoanti-HIVactivityofcervicovaginallavagefluid(CVL)of HIV-resistant(HIV-R)commercialsexworkers(CSWs).Additionally,Tr,andmoresoE,werefoundtoinhibitattachment/entry andtranscytosisofHIV-1inhumanendometrialHEC-1Acells,actingthroughvirusorcells.Giventheirimmunomodulatory activity,wehypothesizedthatTr/Ecouldexertanti-HIV-1activityatmultiplelevels.Here,usingtaggedanduntaggedTr/E proteins,wecomparativelyevaluatedtheirproteaseinhibitory,anti-HIV-1,andimmunomodulatoryactivities,andcellular distribution.Eappearedtofunctionasanautocrine/paracrinefactorinHEC-1Acells,andanti-HIV-1activityofEdepended on its unmodified N-terminus and altered cellular innate activation, but not its antiprotease activity. Specifically, exogenously added N-terminus-unmodified E was able to enter the nucleus and to reduce viral attachment/entry and transcytosis,preferentiallyaffectingR5-HIV-1ADA,butnotX4-HIV-1IIIB.Further,anti-HIV-1activityofEwasassociatedwith significantly decreased HIV-1-triggered IL-8 release, attenuated NF-kB/p65 nuclear translocation, and significantly modulatedmRNAexpressionofinnatesensorsTL