title: Ex Vivo Bioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4(+) T Cells from Aviremic Patients.
abstract: The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4(+) T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4(+) T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4(+) T cells from aviremic HIV-1(+) patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1(+) antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4(+) T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Spivak
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Balch
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: David
authors.initials: D
authors.lastname: Smyth
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Martins
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA vicente.planelles@path.utah.edu.
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D004279:DNA, Viral / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology*; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D004224:Diterpenes; D020536:Enzyme Activators; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C011875:ingenol dibenzoate; D000077767:Panobinostat; D011493:Protein Kinase C