The novel histone deacetylase inhibitors metacept-1 and metacept-3 potently increase HIV-1 transcription in latently infected cells

Abstract

We investigated the ability of several novel class I histone deacetylase inhibitors to activate HIV-1 transcription in latently infected cell lines. Oxamflatin, metacept-1 and metacept-3 induced high levels of HIV-1 transcription in latently infected T cell and monocytic cells lines, were potent inhibitors of histone deacetylase activity and caused preferential cell death in transcriptionally active cells. Although these compounds had potent in-vitro activity, their cytotoxicity may limit their use in patients.

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

“…The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy. However, all clinical trials of HDACi have demonstrated no decline in the frequency of latently infected cells (15,(18)(19)(20).…”

“…Various latencyreversing agents (LRAs) have been investigated, including drugs that trigger the NF-B activation pathway, such as prostratin (10) and bryostatin (11) analogues; BET inhibitors enhancing the binding of the viral Tat protein to the HIV TAR element (12); disulfiram (13,14); and histone deacetylase inhibitors (HDACi), like valproic acid (15,16), vorinostat (17,18), panobinostat (19), and romidepsin (20), that act as epigenetic modifiers. The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy.…”

Characterisation, Evaluation and Clinical Significance of Latent HIV-1 Reservoirs and Therapeutic Strategies for HIV Eradication

“…Oxamflatin, belongs to a novel hydroxamate class of HDAC inhibitor drugs, and has FDA approval in the treatment of solid tumours and haematological malignancies. In the latently infected ACH2 and Jurkat cell lines, it has a EC50 of 3.5uM/L [196] and can induce HIV-1 transcription through the modulation of histone H3 and H4 acetylation in latently infected cells [197]. Another novel HDAC NCH-51 was shown to activate latent HIV-1 gene expression with minimal cytotoxicity, through SP1 sites [198].…”

Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines

“…HEK 293, Jurkat cells, J-Lat Tat-GFP Clone A7 cells were treated with or without Scriptaid or TSA for 24 h, at of 25, 50, 100, 200 and 400 nM. To measure proliferation and viability in the presence of drugs, cells were subjected to an MTT assay (23). In brief, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma) was placed in solution with PBS (5 mg/ml) and used to measure cellular proliferation.…”

“…HDAC-2 and -3 can also associate with the HIV long terminal repeat (LTR), and play a role in the repression of LTR expression (14,17). It has been shown that the disruption of HDAC-1 recruitment to LTR, resulting from the inhibition of HDAC activity by global HDAC inhibitors, leads to LTR activation and the escape of viral expression in both cell line models and primary cells obtained from patients (10,(18)(19)(20)(21)(22)(23)(24)(25)(26). Furthermore, HDAC inhibitor valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA; vorinostat) can induce viral outgrowth from resting CD4 T cells of aviremic patients undergoing HAART (27,28).…”