Search

Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol), that is able to reactivate viral transcription in several models of HIV latency, including J-Lat cells, through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or “shock” drugs, such as protein kinase C (PKC) agonists or histone deacetylase (HDAC) inhibitors. Here, we demonstrate that MMQO activates HIV-1 independently of the Tat transactivator. Gene expression microarrays in Jurkat cells indicated that MMQO treatment results in robust immunosuppression, diminishes expression of c-Myc, and causes the dysregulation of acetylation-sensitive genes. These hallmarks indicated that MMQO mimics acetylated lysines of core histones and might function as a bromodomain and extraterminal domain protein family inhibitor (BETi). MMQO functionally mimics the effects of JQ1, a well-known BETi. We confirmed that MMQO interacts with the BET family protein BRD4. Utilizing MMQO and JQ1, we demonstrate how the inhibition of BRD4 targets a subset of latently integrated barcoded proviruses distinct from those targeted by HDAC inhibitors or PKC pathway agonists. Thus, the quinoline-based compound MMQO represents a new class of BET bromodomain inhibitors that, due to its minimalistic structure, holds promise for further optimization for increased affinity and specificity for distinct bromodomain family members and could potentially be of use against a variety of diseases, including HIV infection., This work was supported by funding from the Spanish Ministry of Economy and Competitiveness (MINECO); the European Regional Development Fund (grant BFU2014-52237-P); Fundación para la Investigación y Prevención del SIDA en España (FIPSE 360946/10; to A.J.); ERC Synergy Grant 609989; Centro de Excelencia Severo Ochoa 2013-2017, SEV-2012-0208; and Plan Nacional BFU2012-37168 (to G.J.F.). The work was also supported in part by the research fund of the First Hospital of Jilin University (Changchun, China), grants from the National Institutes of Health (to M.-M.Z.) and the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC STG 337116 Trxn-PURGE, and Dutch AIDS Fonds grants 2014021 and an ErasmusMC research grant (to T.M.).