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首页> 外文期刊>Nature >Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy
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Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

机译：施用伏立诺他会破坏接受抗逆转录病毒治疗的患者的HIV-1潜伏期

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摘要

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~(4-6), 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.
机译：尽管有抗逆转录病毒疗法，但人类1型免疫缺陷病毒（HIV-1）的前病毒潜伏期仍然是治愈感染的主要障碍〜1。诱导潜伏的CD4〜+ T细胞内潜在基因组的表达是清除该库的主要策略[2,3]。尽管组蛋白脱乙酰基酶抑制剂，例如亚磺酰苯胺异羟肟酸（也称为伏立诺他，VOR）可以在体外破坏HIV-1潜伏期[4-6]，但这种方法的实用性尚未在HIV-被感染的患者。在这里，我们分离了抗逆转录病毒疗法完全抑制了病毒血症的患者的循环静息CD4〜+ T细胞，并直接研究了VOR对这种潜伏性水库的影响。在八名患者中的每位患者中，单剂量的VOR可增加细胞乙酰化的两种生物标志物，并同时诱导静息CD4 +细胞中HIV RNA表达的增加（平均增加4.8倍）。这表明已知可导致HIV潜伏期的分子机制可以在人类中作为治疗靶标，为组蛋白脱乙酰酶抑制剂作为治疗类别提供概念验证，并定义了一种精确方法来测试直接攻击和消除潜在HIV感染的新策略。

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  • 来源
    《Nature》 |2012年第7408期|p.482-485|共4页
  • 作者

    N. M. Archin; A. L. Liberty; A. D. Kashuba; S. K. Choudhary; J. D. Kuruc; A. M. Crooks; D. C. Parker; E. M. Anderson; M. F. Kearney; M. C. Strain; D. D. Richman; M. G. Hudgens; R. J. Bosch; J. M. Coffin; J. J. Eron; D. J. Hazuda; D. M. Margolis;

  • 作者单位

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    HIV Drug Resistance Program, NCI, NIH, Frederick, Maryland 21702, USA;

    HIV Drug Resistance Program, NCI, NIH, Frederick, Maryland 21702, USA;

    VA San Diego Healthcare System and University of California San Diego, San Diego, California 92093, USA;

    VA San Diego Healthcare System and University of California San Diego, San Diego, California 92093, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Harvard School of Public Health, Boston, Massachusetts 02115, USA;

    HIV Drug Resistance Program, NCI, NIH, Frederick, Maryland 21702, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Merck Research Laboratories, White Horse Junction,Pennsylvania 08889, USA;

    The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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