In vitro effects of the small-molecule protein kinase C agonists on HIV latency reactivation

• Published in: Scientific reports 2016-12, Vol.6 (1), p.39032-39032, Article 39032
• Main Authors: Brogdon, Jessica, Ziani, Widade, Wang, Xiaolei, Veazey, Ronald S., Xu, Huanbin
• Format: Article
• Language: English
• Subjects: 13/106; 38/35; 631/154/1438; 692/699/255/1901; Animals; Antiretroviral agents; Antiretroviral therapy; CD4 antigen; Cell activation; Cell survival; Cytotoxicity; Enzyme Activators - chemistry; Enzyme Activators - pharmacology; Gene expression; HIV; HIV Infections - drug therapy; HIV Infections - enzymology; HIV-1 - physiology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Jurkat Cells; Kinases; Latency; Latent infection; Lymphocytes T; Macaca mulatta; Methylation; multidisciplinary; Protein kinase C; Protein Kinase C - metabolism; Science; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - enzymology; Simian Immunodeficiency Virus - physiology; Survival; Virus Activation - drug effects; Virus Latency - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39032

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.