The ingenol-based protein kinase C agonist GSK445A is a potent inducer of HIV and SIV RNA transcription

Author summaryAntiretroviral therapy (ART) is not a definitive cure HIV infection, in part, because the virus is able to integrate its genetic material in the host cell and remain in a dormant but fully replication-competent form during ART. These latently-infected cells can persist for long periods of time and remain hidden from the host's immune system. If ART is stopped, the virus can reactivate from this pool of infected cells and resume HIV replication and disease progression. As such, finding and eliminating cells with latent HIV infection is priority for HIV cure research. One approach is to use compounds referred to as latency-reversing agents, that can induce HIV reactivation during ART. The goal of this approach is to facilitate elimination of infected cells by the virus itself once it reactivates or by the host's immune system, once virus induction renders the cells detectable by the immune system, while also preventing the virus from infecting new cells due to the continued presence of ART. In this study we report on the activity of a novel latency-reversing agent called GSK445A, a potent activator of the enzyme protein kinase C (PKC). We show that GSK445A can induce HIV and simian immunodeficiency virus (SIV) latency reversal in vitro and has a tolerable saftey profile in nonhuman primates that should permit further testing of this PKC-agonist in strategies to cure HIV. Activation of the NF-kappa B signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4(+) T cells from people living with HIV and from SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8(+) T cells, but instead, increased their numbers and enhanced IFN-gamma production in response to HIV peptides. In vivo, GSK445A tolerability was established in SIV-naive RM at 15 mu g/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo. Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission.