Synergistic Activation of Latent HIV-1 Expression by Novel Histone Deacetylase Inhibitors and Bryostatin-1

Abstract

Viral reactivation from latently infected cells has become a promising therapeutic approach to eradicate HIV. Due to the complexity of the viral latency, combinations of efficient and available drugs targeting different pathways of latency are needed. In this work, we evaluated the effect of various combinations of bryostatin-1 (BRY) and novel histone deacetylase inhibitors (HDACIs) on HIV-reactivation and on cellular phenotype. The lymphocyte (J89GFP) or monocyte/macrophage (THP89GFP) latently infected cell lines were treated with BRY, panobinostat (PNB) and romidepsin (RMD) either alone or in combination. Thus, the effect on the viral reactivation was evaluated. We calculated the combination index for each drug combination; the BRY/HDACIs showed a synergistic HIV-reactivation profile in the majority of the combinations tested, whereas non-synergistic effects were observed when PNB was mixed with RMD. Indeed, the 75% effective concentrations of BRY, PNB and RMD were reduced in these combinations. Moreover, primary CD4 T cells treated with such drug combinations presented similar activation and proliferation profiles in comparison with single drug treated cells. Summing up, combinations between BRY, PNB and/or RMD presented a synergistic profile by inducing virus expression in HIV-latently infected cells, rendering these combinations an attractive novel and safe option for future clinical trials.

Novel Latency Reversal Agents for HIV-1 Cure

“…In a majority of these studies, PKC agonists have been combined with LRAs acting through alternative, non-T-cell activating mechanisms. Bryostatin-1 demonstrated synergistic reactivation when combined with the HDAC inhibitors panobinostat, romidepsin and vorinostat in latently infected cell lines (83) and ex vivo in resting CD4 + T cells(28). Bryostatin-1 also synergized with JQ1 in cell lines in vitro and patient cells ex vivo (28; 84).…”

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

“…Prostratin not only induces HIV expression from latently infected cells through phosphorylation and degradation of IκBα, leading to the rapid nuclear translocation of NF-κB35, but also inhibits HIV entry by interacting with a cellular target necessary for viral entry, displaying potent antiviral activity against different strains of HIV-1 and SIV36373839. Likewise, PKC agonist bryostatin-1, isolated from the marine invertebrate Bugula neritina 4041, also shows excellent potential as a therapeutic agent that acts through modulation of PKC signal transduction, as indicated its potency to revert HIV-1 latency via the adenosine monophospate (AMP)-activated protein kinase (AMPK) pathway254243444546. However, recent study of bryostatin-1 treatment shows inhibitory effects on the HIV-specific CD8+ T cells47.…”

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

“…There is a wide consensus that successful latency disruption might require targeting different pathways involved in the maintenance of HIV quiescence. As mentioned, HDAC inhibitors and PKC agonistics have shown in-vitro [32,33] and ex-vivo [23] synergistic activity with bryostatin-1 and in consequence, might be an attractive combination. On the other hand however, HDAC inhibitors have already been shown to induce HIV-1 reactivation from latently infected cells in vivo [7,8].…”