As2O3 enhances retroviral reverse transcription and counteracts Ref1 antiviral activity
As2O3 enhances retroviral reverse transcription and counteracts Ref1 antiviral activity
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DOI：
10.1128/jvi.77.5.3167-3180.2003
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发表时间：
2003-03-01
影响因子：
5.4
通讯作者：
Luban, J
中科院分区：
文献类型：
--
作者：
Berthoux, L;Towers, GJ;Luban, J
像环孢素这样的强效药物已经为信号转导途径以及人类免疫缺陷病毒I型(HIV-1)复制机制提供了有效的探针。最近，用于治疗急性早幼粒细胞白血病(PML)的药物As_2O_3被报道能刺激HIV-1复制。我们发现，As_2O_3加速了HIV-1在人类T细胞中传播的动力学，并在单轮感染后增加了携带HIV-1前病毒的细胞数量。这种刺激作用发生在膜融合后，并导致新合成的病毒cDNA量的稳态水平增加。刺激不依赖于HIV-1em和大多数病毒辅助基因，As2O_3对病毒整合后表达或病毒粒子组装没有检测到的影响。As(2)O(3)对小鼠白血病病毒(MLV)转导的促进作用与HIV-1转导相同，但对Fnu1的限制作用不明显。相反，As_2O_3在很大程度上克服了人Ref1对N嗜性MLV反转录的特异性阻断。As_2O_3破坏PML小体，PML小体是以主要成分PML蛋白质命名的核结构。我们没有观察到HTV-1感染后PML小体的变化。用PML缺失的靶细胞进行的实验表明，PML对HTV-1的感染性没有影响，对As_2O_3的刺激作用是必不可少的。在相同浓度下，三氧化二砷会导致未感染细胞的细胞死亡，从而刺激HIV-1复制。在四种额外的细胞凋亡诱导剂中，只有乙酰氰化物间氯苯肼才能增强HIV-1的感染力，这是一种化合物，与三氧化二砷一样，可以破坏线粒体的跨膜电位。总而言之，三氧化二砷可能通过对线粒体的作用来刺激逆转录病毒的逆转录，并为鉴定Ref1提供了一个有用的工具。
Potent drugs such as cyclosporine have provided effective probes of signal transduction pathways and, as well, of human immunodeficiency virus type I (HIV-1) replication mechanisms. Recently, it was reported that As2O3, a drug used to treat acute promyelocytic leukemia (PML), stimulates HIV-1 replication. We found that As2O3 accelerates the kinetics of a spreading HIV-1 infection in human T cells and increases the number of cells bearing HIV-1 provirus after a single round of infection. The stimulatory effect occurred after membrane fusion and resulted in increased steady-state levels of newly synthesized viral cDNA. Stimulation was independent of HIV-1 em, and most viral accessory genes, and As2O3 had no detectable effects on viral expression postintegration or virion assembly. Murine leukemia virus (MLV) transduction was enhanced by AS(2)O(3) to the same extent as HIV-1 transduction, but As2O3 had no additional effect on Fnu1 restriction. In contrast, As2O3 largely overcame the specific block to N-tropic MLV reverse transcription posed by human Ref1. As2O3 disrupts PML bodies, nuclear structures named for a major component, the PML protein. We observed no changes in PML bodies in response to HTV-1 infection. Experiments with PML-null target cells indicated that PML has no effect on HTV-1 infectivity and is dispensable for the stimulatory effect of As2O3. As2O3 caused cell death in uninfected cells at the same concentrations which stimulate HIV-1 replication. Among four additional apoptosis-inducing agents, a boost in HIV-1 infectivity was observed only with carbonyl cyanide m-chlorophenylhydrazone, a compound which, like As2O3, disrupts the mitochondrial transmembrane potential. In summary, As2O3 stimulates retroviral reverse transcription, perhaps via effects on mitochondria, and provides a useful tool for characterizing Ref1.