Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

Abstract

Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

“…Indeed, several pre-clinical and clinical studies have reported that bryostatin 1 can alter the immunophenotype and increase the immunogenicity of cancer cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL) 17,[26][27][28][29][30][31] . These and related studies by a Spaner-Wender collaboration on CLL antigen expression and by a Zack-Marsden-Wender collaboration on CD69 expression in CD4+ T cells, the latter related to HIV eradication, indicate that PKC modulators can enhance expression and persistence of certain antigens, potentially enhancing a variety of (neo)antigen-targeted therapies 17,30,[32][33][34] .…”

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

“…A number of additional HDACIs with latency reversing activity have emerged from screens involving compounds from natural sources, including largazole and psammaplin A (Figure and Table ), which were identified in screens of class‐specific HDACIs, and chemical libraries from marine invertebrates and microorganisms (Tables and ) . Largazole (Figure ), originally isolated from marine cyanobacteria, is a well‐known antiproliferation agent with specificity toward class I HDAC enzymes, and showed significant synergy for HIV‐1 provirus reactivation with analogs of bryostatin‐1, and produced minimal toxicity, when examined on J‐Lat reporter cell lines and resting CD4 + T cells . Psammaplin (Figure ), which is also a class I HDAC inhibitor with antitumor activity was identified in a screen for LRAs from a library of natural compounds derived from marine invertebrates and microorganisms (Tables and ) .…”

“…Additional important considerations include a requirement for minimal toxicity, and negligible effects on global T cell activation. Furthermore, there is increasing recognition that no single LRA is likely capable of inducing the full spectrum of latent provirus required to purge a sufficient fraction of infected cells, and therefore most recent efforts have focused on developing and characterizing combinations of compounds that produce synergistic effects on reactivation of individual provirus, and exert a broader effect on the latently infected population as a whole …”

“From Large-Scale Collections to the Potential Use of Genomic Techniques for Supply of Drug Candidates”

“…This work should be read in conjunction with two excellent reviews published by Wender et al (2014Wender et al ( , 2015, that demonstrated the ability, using modern synthetic techniques, to produce very active bryostatin variants, with an example being the third generation analog (Figure 3; 10). As a result of having readily available bryostatin 1, Wender and collaborators have now demonstrated that this bryostatin 1 and subtle variations such as SUW 133 (Figure 3; 11), can release latent HIV from cell depots in patients (Albert et al, 2017;Marsden et al, 2017).…”

“…Since synthetic bryostatin 1 and derivatives are now available on a reasonable scale (Wender et al, 2014(Wender et al, , 2015 with these new synthetic techniques, coupled to the ability to make modifications easily, then the biological activities of this class of compounds will definitely increase. As an example, recently there were reports of activity against HIV virus that has been "sequestered" in dendritic cells (Albert et al, 2017;Marsden et al, 2017). To finish this section, although the biosynthetic gene clusters have been identified, no work has yet been reported on cloning of these clusters in a surrogate host, and then coupled to production by fermentation.…”