Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy
M. F. Kearney, A. D. Kashuba, A. L. Liberty, R. J. Bosch, D. M. Margolis, A. M. Crooks, J. J. Eron, M. C. Strain, Sarita Choudhary, D. D. Richman, N. M. Archin, M. G. Hudgens, E. M. Anderson, J. D. Kuruc, J. M. Coffin, D. J. Hazuda, D. C. Parker
Abstract
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.