Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal
EBioMedicine , Volume 3 p. 108- 121
Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4. + T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal.
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|Organisation||Department of Internal Medicine|
Stoszko, M.L, De Crignis, E, Rokx, C, Khalid, M.M, Lungu, C, Palstra, R.-J.T.S, … Mahmoudi, T. (2016). Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal. EBioMedicine, 3, 108–121. doi:10.1016/j.ebiom.2015.11.047