The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. Prior attempts at purging viral reservoirs have included T cell mitogens or histone deacetylase inhibitors (HDACIs) with limited success in reducing the viral reservoir, underscoring the need for additional approaches that promote viral reactivation. This proposal is motivated by our recent discovery [1] that a small molecule, JQ1, initially identified as a potent bromodomain-4 (Brd4) antagonist and cancer suppressor, potently upregulates latent and induced HIV proviral expression in cell lines and primary CD4+ T cells. In addition, JQ1 suppresses systemic inflammatory cytokine production in mice acutely exposed to endotoxin and suppresses T cell activation genes in primary CD4+ T cells. JQ1 therefore represents a novel compound with desirable features and translational utility. Our overall hypothesis is that JQ1 promotes viral reactivation and suppresses NF-kB driven gene expression by modulating Brd4 activity. As a result of interfering with Brd4 activity at the HIV promoter, JQ1 may increase access of the viral Tat protein to the host positive transcriptional elongation factor (P-TEFb). At cytokine gene promoters, we hypothesize that JQ1 interferes with acetylated p65/RelA interaction with Brd4 resulting in declines in NF- B driven cytokine gene expression, but not NFAT driven gene expression. To address our hypothesis, we propose a translational program to characterize this compound's effect on HIV proviral reactivation and on cytokine gene expression in latent T cell lines, an in vitro latency model for primary T cells and in resting CD4+ T cells from infected individuals receiving effective ART.
Despite the profound success of HAART, viral reservoirs and chronic inflammation persist, necessitating lifelong treatment and increased risk for inflammation associated comorbidities. We describe a proposal to evaluate a novel compound JQ1 that displays potent HIV reactivation and cytokine gene suppression. This may have translational relevance for novel strategies to purge viral reservoirs, within a favorable context of inflammatory cytokine suppression.
