Epigenetic regulation of HIV-1 latency by cytosine methylation.
Epigenetic regulation of HIV-1 latency by cytosine methylation.
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DOI：
10.1371/journal.ppat.1000495
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Verdin E
中科院分区：
文献类型：
--
作者：
Kauder SE;Bosque A;Lindqvist A;Planelles V;Verdin E
人类免疫缺陷病毒1型（HIV-1）在接受高效抗逆转录病毒疗法（HAART）治疗的感染者的静息CD4 + T细胞内持续处于潜伏状态。为了清除感染，必须消除这个储存库。使用cDNA文库筛选，我们已经确定甲基-CpG结合域蛋白2（MBD2）作为HIV-1潜伏期的调节剂。两个CpG岛位于HIV-1转录起始位点的侧翼，并在潜伏感染的Jurkat细胞和原代CD4 + T细胞中甲基化。MBD2和组蛋白脱乙酰基酶2（HDAC2）在潜伏期期间在这些CpG岛之一处被发现。用5-氮杂-2 ′脱氧胞苷（aza-CdR）抑制胞嘧啶甲基化可消除MBD 2和HDAC 2的募集。此外，aza-CdR与NF-κ B激活剂prostratin或TNF-α有效协同，以重新激活潜伏的HIV-1。这些观察结果证实，胞嘧啶甲基化和MBD2是HIV-1潜伏期的表观遗传调节因子。通过将DNA甲基化抑制剂如aza-CdR和NF-κ B激活剂纳入目前的抗病毒治疗中，可以增强HIV-1从感染者中的清除。目前的药物疗法抑制人类免疫缺陷病毒（HIV）的复制。在接受这些治疗的患者中，艾滋病毒的数量减少到无法检测的水平，艾滋病毒相关疾病消退。然而，停止抗病毒药物治疗会导致艾滋病毒和疾病的快速复发。其中一个原因是潜伏感染的细胞，其中病毒复制暂时停止。当药物治疗停止时，来自这些潜伏感染细胞的病毒可以恢复感染并传播到患者的其他细胞，导致疾病复发。在这里，我们证明了潜伏机制之一是DNA甲基化，其中称为甲基的化学基团被添加到HIV DNA中。我们还鉴定了一种称为甲基-CpG结合域蛋白2（MBD2）的宿主蛋白，它结合甲基化的HIV DNA，是潜伏期的重要介质。此外，我们证明了一种抑制DNA甲基化的药物可以有效地重新激活潜伏的HIV。新的战略，以消除或减少潜在的水库是必要的。我们的研究结果可能有助于开发新的疗法，以有效地重新激活潜伏的HIV-1，从而使其对目前的药物治疗敏感。
Human immunodeficiency virus type 1 (HIV-1) persists in a latent state within resting CD4+ T cells of infected persons treated with highly active antiretroviral therapy (HAART). This reservoir must be eliminated for the clearance of infection. Using a cDNA library screen, we have identified methyl-CpG binding domain protein 2 (MBD2) as a regulator of HIV-1 latency. Two CpG islands flank the HIV-1 transcription start site and are methylated in latently infected Jurkat cells and primary CD4+ T cells. MBD2 and histone deacetylase 2 (HDAC2) are found at one of these CpG islands during latency. Inhibition of cytosine methylation with 5-aza-2′deoxycytidine (aza-CdR) abrogates recruitment of MBD2 and HDAC2. Furthermore, aza-CdR potently synergizes with the NF-κB activators prostratin or TNF-α to reactivate latent HIV-1. These observations confirm that cytosine methylation and MBD2 are epigenetic regulators of HIV-1 latency. Clearance of HIV-1 from infected persons may be enhanced by inclusion of DNA methylation inhibitors, such as aza-CdR, and NF-κB activators into current antiviral therapies. Current drug therapies inhibit replication of the human immunodeficiency virus (HIV). In patients undergoing these therapies, the amount of HIV is reduced to an undetectable level and HIV-related disease subsides. However, stopping antiviral drug therapy results in the quick return of HIV and of disease. One reason for this is latently infected cells, in which virus replication is temporarily halted. When drug therapy is stopped, virus from these latently infected cells can resume infection and spread to other cells in the patient, resulting in the return of disease. Here, we demonstrate that one mechanism of latency is DNA methylation, in which chemical groups called methyl groups are added to HIV DNA. We also identify a host protein called methyl-CpG binding domain protein 2 (MBD2) that binds methylated HIV DNA and is an important mediator of latency. Furthermore, we demonstrate that a drug that inhibits DNA methylation potently reactivates latent HIV. Novel strategies to eliminate or reduce the latent reservoir are necessary. Our findings may prove useful in the development of novel therapies to efficiently reactivate latent HIV-1, thus making it susceptible to current drug therapies.
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影响因子：
158.5
作者：
Gulick, RM;Mellors, JW;Chodakewitz, JA
通讯作者：
Chodakewitz, JA
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
6.7
作者：
Andersen JL;DeHart JL;Zimmerman ES;Ardon O;Kim B;Jacquot G;Benichou S;Planelles V
通讯作者：
Planelles V
影响因子：
5.4
作者：
Coull, JJ;Romerio, F;Margolis, DM
通讯作者：
Margolis, DM
DOI：
10.1073/pnas.86.7.2365
发表时间：
1989-04-01
影响因子：
11.1
作者：
FOLKS, TM;CLOUSE, KA;FAUCI, AS
通讯作者：
FAUCI, AS