Elimination of HIV-1 latently infected cells by PKC agonist gnidimacrin alone and in combination with an HDAC inhibitor. 21st International AIDS Conference (AIDS 2016). July 2016
Abstract category: A57 Targeting HIV persistence during ART (cure strategies)
Title: Elimination of HIV-1 latently infected cells by PKC agonist gnidimacrin alone and in combination with a histone deacetylase inhibitor
Authors: L. Huang, W. Lai, L. Zhu, C.-H. Chen
Institution(s): Duke University Medical Center, Surgery, Durham, United States
Text: Background: Several classes of HIV-1 latency reversing agents (LRAs) including PKC agonists and HDACis have been investigated for their effects against latent HIV-1 infection. Although many LRAs were capable of reactivating latent HIV-1, it is less certain if they can actually reduce the latent viral reservoirs. To identify potent LRAs that can effectively eliminate/reduce latent HIV-1 reservoirs, we investigated the PKC agonist gnidimacrin (GM) alone and in combination with a selective HDAC inhibitor thiophenyl benzamide (TPB) for their effectiveness on elimination of HIV-1 latently infected cells.
Methods: 1) cell line model: U1 cells were treated with various concentrations of GM with/without the presence of TPB. The culture supernatant was then collected for P24 ELISA to quantify latent HIV-1 activation; 2) ex vivo model: PBMCs from HIV+ patients (with >5 years of ART and undetectable viral load) were treated with GM, GM+TPB, or vorinostat in the presence of anti-retroviral agents. The viral DNA in the lately infected cells were quantified with RT-PCR and the frequency of latently infected cells was determined by using a limiting dilution viral outgrowth assay.
Results: In U1 model, the EC50 of GM was 18 pM for latent viral activation and its potency was enhanced about three-fold in the presence of TPB. In ex vivo model, GM alone (20 pM) was able to reduce pro-viral DNA and the frequency of latently infected cells by 5-10 folds. Addition of TPB further increased the effect of GM by over three-fold.
Conclusions: The results of this study demonstrate that GM is an extremely potent LRA that can effectively reduce HIV-1 latently infected cells ex vivo at pM concentrations. In the presence of TPB, the effect of GM was further enhanced. TPB exhibited good selectivity with no overlapping cytotoxic and effective doses in contrast to other tested HDACIs. Moreover, TPB may antagonize the potential side effects of GM by inhibiting high dose GM-induced inflammatory cytokine production. Thus, combination of GM and TPB provides a unique and effective option in reducing the latent HIV-1 reservoir.
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