Publication Date:
2012-07-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704185/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704185/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- AI084553/AI/NIAID NIH HHS/ -- AI095052/AI/NIAID NIH HHS/ -- AI096113/AI/NIAID NIH HHS/ -- AI50410/AI/NIAID NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- R34 AI084553/AI/NIAID NIH HHS/ -- RR024383/RR/NCRR NIH HHS/ -- U01 AI095052/AI/NIAID NIH HHS/ -- U19 AI096113/AI/NIAID NIH HHS/ -- UL1 RR025747/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22837004" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation/drug effects
;
Anti-HIV Agents/*therapeutic use
;
Biomarkers/metabolism
;
CD4-Positive T-Lymphocytes/cytology/drug effects/metabolism/virology
;
Gene Expression Regulation, Viral/drug effects
;
HIV Infections/blood/*drug therapy/*virology
;
HIV-1/*drug effects/genetics/*growth & development
;
Histone Deacetylase Inhibitors/administration & dosage/adverse
;
effects/pharmacology
;
Histones/drug effects/metabolism
;
Humans
;
Hydroxamic Acids/administration & dosage/adverse effects/*pharmacology
;
Proviruses/drug effects/genetics/growth & development
;
RNA, Viral/biosynthesis/blood
;
Risk Assessment
;
Up-Regulation/drug effects
;
Viremia/drug therapy/virology
;
Virus Latency/*drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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