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

Jessica Brogdon, Widade Ziani, Xiaolei Wang, Ronald S Veazey, Huanbin Xu
Scientific Reports 2016 December 12, 6: 39032
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.

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