Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy

Abstract

Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

“…These include the HDACis vorinostat (Archin et al, 2017; Archin et al, 2012; Elliott et al, 2014), panobinostat (Rasmussen et al, 2014) and romidepsin (Sogaard et al, 2015), the disulfiram drug shown to affect PI3K/Akt and more commonly used to treat alcoholism (Elliott et al, 2015; Spivak et al, 2014; Xing et al, 2011), and the TLR9 agonist MGN1703 (Vibholm et al, 2017). The PKC agonist bryostatin was also evaluated in vivo but had no effect on the transcription of latent HIV (Gutierrez et al, 2016). In these clinical studies, all LRAs except bryostatin increased HIV RNA transcription when administered alone, but there was no decline in the number of infected cells (Archin et al, 2012; Elliott et al, 2015; Elliott et al, 2014; Gutierrez et al, 2016; Rasmussen et al, 2014; Sogaard et al, 2015).…”

“…The PKC agonist bryostatin was also evaluated in vivo but had no effect on the transcription of latent HIV (Gutierrez et al, 2016). In these clinical studies, all LRAs except bryostatin increased HIV RNA transcription when administered alone, but there was no decline in the number of infected cells (Archin et al, 2012; Elliott et al, 2015; Elliott et al, 2014; Gutierrez et al, 2016; Rasmussen et al, 2014; Sogaard et al, 2015). In one clinical trial, the combination of the HDACi romidepsin with a T-cell vaccine led to a modest reduction in HIV DNA, although the mechanism for this reduction was not explored (Leth et al, 2016).…”

“…To date, clinical trials with LRAs have demonstrated that activation of viral gene expression is possible in vivo, but there is limited or no clearance of the reactivated cells (Archin et al, 2017; Archin et al, 2012; Elliott et al, 2015; Elliott et al, 2014; Gutierrez et al, 2016; Rasmussen et al, 2014; Sogaard et al, 2015). To promote the turnover of reactivated cells, immune based strategies including antibodies, T-cell vaccines and immunotherapeutics that enhance T-cell function, are being investigated to kill reactivated cells following latency reversal (reviewed elsewhere (Brockman et al, 2015; Marsden & Zack, 2015; Wykes & Lewin, 2017)).…”

HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

“…However, direct quantitation of cell-associated viral protein following clinical administration of HDACis has not been possible. Other agents, such as bromodomain inhibitors and protein kinase C (PKC) agonists, have also been shown to induce viral transcription in vitro and in preclinical models and are under further evaluation as potential clinical HIV "shock" agents (6,(12)(13)(14)(15)(16). Worth noting, the induction of viral protein expression is a prerequisite for several investigational immune-mediated "kill" strategies (3)(4)(5).…”

HIV Latency Reversal Agents: Effective for Cure?

“…Protein kinase activators like Bryostatin, Ingenols and Prostratin were among the initial members to demonstrate in vitro activation of engineered cell lines bearing HIV proviruses. Their unacceptable cytotoxicity limitations [8,9] prevented their trials in vivo or resulted in failure of HIV rebound in performed trial [10]. However modified bryostatin analogs with lowered toxicity have recently shown promising viral rebound in engineered humanized BLT mice [11].…”