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

• Published in: Nature (London) Vol. 487; no. 7408; pp. 482 - 485
• Main Authors: Archin, N. M., Liberty, A. L., Kashuba, A. D., Choudhary, S. K., Kuruc, J. D., Crooks, A. M., Parker, D. C., Anderson, E. M., Kearney, M. F., Strain, M. C., Richman, D. D., Hudgens, M. G., Bosch, R. J., Coffin, J. M., Eron, J. J., Hazuda, D. J., Margolis, D. M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2012; Nature Publishing Group
• Subjects: 631/154/436; 631/250/255/1901; 692/700/565; Acetylation - drug effects; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral agents; Antiretroviral drugs; Antiviral agents; Biological and medical sciences; Biomarkers - metabolism; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell culture; Drug dosages; Drug therapy; Gene Expression Regulation, Viral - drug effects; Genomes; Health aspects; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - adverse effects; Histone Deacetylase Inhibitors - pharmacology; Histones - drug effects; Histones - metabolism; HIV; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - virology; HIV patients; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - growth & development; Human immunodeficiency virus; Human immunodeficiency virus 1; Humanities and Social Sciences; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - adverse effects; Hydroxamic Acids - pharmacology; Inhibitors; letter; Lymphocytes; Medical sciences; multidisciplinary; Pharmacology. Drug treatments; Physiological aspects; Plasma; Proviruses - drug effects; Proviruses - genetics; Proviruses - growth & development; Risk Assessment; RNA, Viral - biosynthesis; RNA, Viral - blood; Science; Science (multidisciplinary); Up-Regulation - drug effects; Viremia - drug therapy; Viremia - virology; Virus Latency - drug effects; Vorinostat; United States; Virus; Infection; Antiretroviral agent; Chemotherapy; Histone deacetylase inhibitor; Treatment; Retroviridae; Human immunodeficiency virus; Mechanism of action; Lentivirus; Latency
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11286

The latent HIV-1 reservoir represents a major barrier to curing patients with HIV-1 infection, and now in vivo evidence is presented that vorinostat can disrupt proviral latency of HIV-1. Beating HIV latency A major barrier to achieving a cure in patients infected with HIV-1 is the ability of the HIV genome to integrate into the DNA of resting CD4 + T cells and adopt a state of latency, evading both immune detection and pharmaceutical attack. It was shown previously that induction of virus gene expression in latently HIV-1-infected cells can be achieved in vitro with histone deacetylase inhibitors such as vorinostat, a drug used to treat cutaneous lymphoma. In this study, the authors report the first in vivo evidence that vorinostat can disrupt proviral latency of HIV-1. Vorinostat has some toxic effects that would need to be considered when assessing the risks and benefits of attempts to eradicate HIV infection using this or similar drugs. 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 , 3 . Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro 4 , 5 , 6 , 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.