title: Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation.
abstract: Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676-PKCδ/θ-IκBα/ε-NF-κB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies.
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America.
authors.forename: Guochun
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Mendes
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America; San Francisco Veterans Affairs Medical Center (VMAC), San Francisco, California, United States of America.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaiser
authors.affiliation: San Francisco Veterans Affairs Medical Center (VMAC), San Francisco, California, United States of America; Department of Physics, Williams College, Williamstown, Massachusetts, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Wong
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, California, United States of America.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America.
authors.forename: Ivy
authors.initials: I
authors.lastname: Cai
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Fenton
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Melcher
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, California, United States of America.
authors.forename: James E K
authors.initials: JE
authors.lastname: Hildreth
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America; Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: George R
authors.initials: GR
authors.lastname: Thompson
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wong
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, California, United States of America; Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
mesh_terms: D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*
chemical_list: C561695:(+)-JQ1 compound; C486592:3-ingenyl angelate; D001381:Azepines; D004224:Diterpenes; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014230:Triazoles; D000072000:NF-KappaB Inhibitor alpha; D042925:Positive Transcriptional Elongation Factor B