The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb

Abstract

None of the currently used anti-HIV-1 agents can effectively eliminate latent HIV-1 reservoirs, which is a major hurdle to a complete cure for AIDS. We report here that a novel oral BET inhibitor OTX015, a thienotriazolodiazepine compound that has entered phase Ib clinical development for advanced hematologic malignancies, can effectively reactivate HIV-1 in different latency models with an EC 50 value 1.95-4.34 times lower than JQ1, a known BET inhibitor that can reactivate HIV-1 latency. We also found that OTX015 was more potent when used in combination with prostratin. More importantly, OTX015 treatment induced HIV-1 full-length transcripts and viral outgrowth in resting CD4 + T cells from infected individuals receiving suppressive antiretroviral therapy (ART), while exerting minimal toxicity and effects on T cell activation. Finally, biochemical analysis showed that OTX015-mediated activation of HIV-1 involved an increase in CDK9 occupancy and RNAP II C-terminal domain (CTD) phosphorylation. Our results suggest that the BET inhibitor OTX015 may be a candidate for anti-HIV-1-latency therapies.

Specific and Stable Suppression of HIV Provirus Expression In Vitro by Chimeric Zinc Finger DNA Methyltransferase 1

“…YA cells and C11 cells, which are HIV-1-infected or latently infected Jurkat T cells, respectively, were first created in our laboratory and are now used widely in the research community 36, 37, 51, 52, 53, 54. The C11 and YA cells were maintained in RPMI 1640 medium supplemented with 10% (v/v) fetal bovine serum (Gibco), 100 U mL −1 penicillin, and 100 μg mL −1 streptomycin (Invitrogen) at 37°C under 5% CO 2 .…”

Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo

“…Bromodomain inhibitors have been shown to activate HIV-1 gene expression in different cell systems in vitro with latent or chronic HIV-1 infection (24-27). However, little is known about how bromodomain inhibitors affect HIV-1 reservoirs in vivo during cART.…”

Cancer therapies in HIV cure research

“…OTX015 induced HIV production in resting CD4+ T-cells from HIV-infected individuals on ART [25] and both OTX015 [25] and JQ1 [16, 22] displayed synergy ex vivo when combined with low dose protein kinase C (PKC) agonists. Overall, BET inhibitors clearly have pharmacological potential to activate HIV from latency, which may be enhanced in combination with other LRAs, but the current lack of clinical safety and pharmacokinetic data is likely to limit their immediate development for HIV cure studies.…”