Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal

• BAF complex inhibitors (BAFi's) activate latent HIV-1 in cell line models of latency.
• BAFi's in combination with HDAC inhibitors and PKC activators synergistically activate latent HIV-1.
• The BAFi's PYR and CAPE reverse HIV-1 latency in primary cell models of latency and in cells obtained from HIV-1 patients.Access to Combination antiretroviral therapy (cART) has made HIV-1 infection a chronic disease. However, cART is not curative, as a small number of infected cells harboring silent virus with potential to renew the infection persist despite cART. Efforts to cure HIV-1 include activation of these latent cells, making them susceptible to immune clearance. Here we describe the activity of BAF inhibitors in HIV-1 activation in in vitro models of HIV-1 latency as well as in cells obtained from HIV-1 infected patient volunteers. Our data highlight the clinical potential of BAF inhibitors for inclusion in combinatorial therapy to reverse HIV-1 latency.

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.