Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation

Abstract

Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676-PKCδ/θ-IκBα/ε-NF-κB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies.

Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells

“…It is not known whether this enhancement will occur with the non-globally activating LRAs currently being examined in clinical trials. Many studies are now assessing potential synergistic combinations of different LRAs to achieve more robust latency reactivation, of which some have shown promising results (44,45).…”

Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition

“…1, E and F (15). This could be attributed partially to global T cell activation and the absence of cytotoxic T lymphocyte (CTL) response (16,17).…”

Might dolutegravir be part of a functional cure for HIV?

“…The latencyreversing agents mainly include histone deacetylase inhibitors, methylation inhibitors, and cytokine (e.g., interleukin-7). Recently, it was reported that ingenol-3-angelate (PEP005), a FDA-approved anticancer drug, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity (Jiang et al 2015). These compounds are potential candidates for advancing HIV eradication.…”