Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex.
Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex.
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DOI：
10.1371/journal.ppat.1004040
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发表时间：
2014-04
期刊：
影响因子：
6.7
通讯作者：
Giam CZ
中科院分区：
文献类型：
--
作者：
Philip S;Zahoor MA;Zhi H;Ho YK;Giam CZ
人类嗜T淋巴细胞病毒I型（HTLV-I）感染在感染者中很大程度上是潜伏的。HTLV-1如何建立潜伏期和重新激活尚不清楚。在这里，我们表明，大多数HTLV-1感染的HeLa细胞变得衰老。相比之下，当NF-κB活性被阻断时，衰老被避免，感染的细胞继续分裂并长期产生病毒蛋白。一小群感染的NF-κ B正常HeLa细胞表达低但可检测水平的Tax和雷克斯，尽管不是Gag或Env。在这些“潜伏”感染的细胞中，Tax对HTLV-1 LTR的反式激活持续存在，但NF-κB反式激活由于HTLV-1反义蛋白HBZ的抑制而减弱。此外，Gag-Pol mRNA主要定位于这些细胞的细胞核中。重要的是，发现HBZ抑制Rex介导的含内含子mRNA的输出。过表达雷克斯或shRNA介导的HBZ沉默导致病毒再激活。重要的是，强烈的NF-κB抑制也会重新激活HTLV-1。因此，在HTLV-1感染期间，当Tax/雷克斯表达相对于HBZ是稳健的和占优势的时，生产性感染伴随着结构蛋白的表达和NF-κB过度活化，其诱导衰老。当Tax/雷克斯表达被抑制而HBZ占优势时，潜伏感染建立为表达调节蛋白（Tax/雷克斯/HBZ）而非结构蛋白。HBZ通过下调Tax诱导的NF-κB活化和衰老以及抑制Rex介导的病毒结构蛋白表达来维持病毒潜伏期。大多数HTLV-1感染者无症状。据认为，前病毒DNA是转录惰性的，HTLV-1通过宿主细胞的有丝分裂扩增进行复制。然而，HTLV-1携带者中不断发展的前病毒整合模式表明新的感染不断发生。HTLV-1是否或如何建立潜伏期并重新激活尚不清楚。我们发现，HTLV-1感染在文化中可以导致两种替代的结果-生产性感染伴随着衰老或潜伏感染，然后克隆扩张-根据调节蛋白的相对表达：税收，雷克斯，HBZ。HTLV-1潜伏期由HBZ建立，而再激活由雷克斯通过调节病毒mRNA的核输出来实现。阐明HTLV-1潜伏和再活化的潜在机制可以促进病毒控制，以防止疾病进展。
Human T lymphotropic virus type I (HTLV-I) infection is largely latent in infected persons. How HTLV-1 establishes latency and reactivates is unclear. Here we show that most HTLV-1-infected HeLa cells become senescent. By contrast, when NF-κB activity is blocked, senescence is averted, and infected cells continue to divide and chronically produce viral proteins. A small population of infected NF-κB-normal HeLa cells expresses low but detectable levels of Tax and Rex, albeit not Gag or Env. In these “latently” infected cells, HTLV-1 LTR trans-activation by Tax persists, but NF-κB trans-activation is attenuated due to inhibition by HBZ, the HTLV-1 antisense protein. Furthermore, Gag-Pol mRNA localizes primarily in the nuclei of these cells. Importantly, HBZ was found to inhibit Rex-mediated export of intron-containing mRNAs. Over-expression of Rex or shRNA-mediated silencing of HBZ led to viral reactivation. Importantly, strong NF-κB inhibition also reactivates HTLV-1. Hence, during HTLV-1 infection, when Tax/Rex expression is robust and dominant over HBZ, productive infection ensues with expression of structural proteins and NF-κB hyper-activation, which induces senescence. When Tax/Rex expression is muted and HBZ is dominant, latent infection is established with expression of regulatory (Tax/Rex/HBZ) but not structural proteins. HBZ maintains viral latency by down-regulating Tax-induced NF-κB activation and senescence, and by inhibiting Rex-mediated expression of viral structural proteins. Most HTLV-1-infected individuals are asymptomatic. It is thought that the proviral DNA is transcriptionally inert and HTLV-1 replicates through mitotic expansion of host cells. The evolving provirus integration patterns in HTLV-1 carriers, however, suggest new infection occurs continuously. Whether or how HTLV-1 establishes latency and reactivates is unclear. We show that HTLV-1 infection in culture can lead to two alternative outcomes — productive infection accompanied by senescence or latent infection followed by clonal expansion — based on the relative expression of regulatory proteins: Tax, Rex, and HBZ. HTLV-1 latency is established by HBZ, and reactivation is achieved by Rex through regulating nuclear export of viral mRNAs. Elucidating mechanisms underlying HTLV-1 latency and reactivation can facilitate virus control to prevent progression to disease.
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