title: In vitro effects of the small-molecule protein kinase C agonists on HIV latency reactivation.
abstract: The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques. The results showed that PKC agonists increased cell activation with different degrees of latency reactivation, concomitant with reduced levels of histone methylation. With increasing concentrations, prostratin and byrostain-1 treatment rapidly reduced cell survival and cell activation. The PKC agonist combinations, or in combination with JQ1, led to modest levels of synergistic reactivation of HIV. Remarkably, PEP005 treatment alone caused marked reactivation of HIV latency, similar to PMA stimulation. These findings suggested that PEP005 alone, as indicated its lower cytotoxicity and lower effective dose inducing maximal reactivation, might be a candidate for effectively reactivating HIV latency as part of a therapeutic strategy for HIV infection.
authors.affiliation: Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Brogdon
authors.affiliation: Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433, USA.
authors.forename: Widade
authors.initials: W
authors.lastname: Ziani
authors.affiliation: Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.affiliation: Tulane National Primate Research Center, Pathology and Laboratory Medicine, Tulane University School of Medicine, Covington, LA 70433, USA.
authors.forename: Huanbin
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008253:Macaca mulatta; D011493:Protein Kinase C / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000201:enzymology; D015302:Simian Immunodeficiency Virus / Q000502:physiology; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D020536:Enzyme Activators; D011493:Protein Kinase C