Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection [1]. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir [2]. While histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA or vorinostat, VOR) can disrupt HIV-1 latency in vitro [3–5], the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Therefore we isolated the circulating resting CD4+ T cells of patients in whom viremia was fully suppressed by antiretroviral therapy (ART), and directly studied the effect of VOR in this latent reservoir. In each of eight patients studied, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase 4.8-fold). This is the first demonstration that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in man, provides proof-of-concept for HDAC inhibitors as a new therapeutic class, and defines a precise approach to test novel strategies to directly attack and eradicate latent HIV infection.