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

NM Archin, AL Liberty, AD Kashuba, SK Choudhary… - Nature, 2012 - nature.com
NM Archin, AL Liberty, AD Kashuba, SK Choudhary, JD Kuruc, AM Crooks, DC Parker…
Nature, 2012nature.com
Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-
1) remains a principal obstacle to curing the infection. Inducing the expression of latent
genomes within resting CD4+ T cells is the primary strategy to clear this reservoir,. Although
histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as
vorinostat, VOR) can disrupt HIV-1 latency in vitro,,, the utility of this approach has never
been directly proven in a translational clinical study of HIV-infected patients. Here we …
Abstract
Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir,. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro,,, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4+ T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, 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 demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
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