PKC Agonists 12 PKC isoforms All PKC isoforms are notequal Ingenol mebutate angelate is FDA approved forthe treatment of actinic keratosis Ingenol derivatives testedING mebutateING coreING B 3capro ID: 607735
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Ingenol efficiently reactivates latent HIV in cells from aviremic patients” Vicente Planelles, PhDDivision of Microbiology and ImmunologyDepartment of Pathology PKC Agonists 12 PKC isoforms All PKC isoforms are notequal Ingenol mebutate (angelate) is FDA approved forthe treatment of actinic keratosis Ingenol derivatives testedING mebutateING coreING B (3caproyl)ING mebutate Ingenol 3.20 dibenzoate in the Tmodel ReactivationinducedbyLRAsprimarycellmodellatencyCulturedweretreatedwitheitherSAHAnMBryostatinnMIngenolnMoranti/CDforandreactivationwasmeasuredintracellularGag L. Martins and A. Bosque3,20 dibenzoate Ingenol core and derivativesin T 0.20.40.60.81.21.41.61.8% Cells P24+Ingenol DibenzoateMebutateIngenolCoreErin Larragoite CD3/CD28Medium 10µM 1µM 100nM 10nM REVEAL (apid ivo valuation of nti atency) 180mL whole blood from healthy aviremic HIVvolunteer FicollrCD4 negative isolation rCD4s in 1mL medium in 24well plate 48 hour incubation under different LRA Adam Spivak HIV1 gRNA qPCR in sup. Shan, Siliciano et al., JVI 2013 A. Spivak and A. BosqueIngenol DB in aviremic patient cells(REVEAL assay) A. Spivak and A. Bosque Ingenol DB in aviremic patient cells REVEALassay) Cytokine secretion (ING DB) Adam Spivak PKC Agonists CONCLUSIONS & FUTURE DIRECTIONS Ingenols,promisingLRAsPotency approximates that of antiCD3/28No toxicity in primary T cells Donordependent cytokine secretion in human patient cellsMechanism: what accounts for differences in apoptosis, cytokine secretion, reactivation ?Transcriptomeanalysis (Topher Woelk)PKC isoform analysis (Martins/Bosque/SpivakEffects on chromatin/transcription AlbertoBosqueLauraMartinsFunding: NIAIDNot in the picture:Adam SpivakPeter RamirezErin LarragoiteMckenna Kimball