HIV-1 transcripts use IRES-initiation under conditions where Cap-dependent translation is restricted by poliovirus 2A protease.
HIV-1 transcripts use IRES-initiation under conditions where Cap-dependent translation is restricted by poliovirus 2A protease.
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DOI：
10.1371/journal.pone.0088619
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
da Costa LJ
中科院分区：
文献类型：
--
作者：
Amorim R;Costa SM;Cavaleiro NP;da Silva EE;da Costa LJ
在HIV-1复制周期中合成的30种不同种类的mRNA都被加帽和聚腺苷酸化。在HIV-1 mRNA的5′端非翻译区发现了内部核糖体进入位点，这可能是一种新的mRNA翻译起始机制。然而，Cap依赖性翻译被认为是驱动HIV-1蛋白合成起始的主要机制。在这项工作中，我们描述了一种细胞系统，其中较低至较高水平的脊髓灰质炎病毒2A蛋白酶的瞬时表达强烈抑制细胞Cap依赖性翻译，在72小时的时间范围内对细胞没有毒性作用。在该系统中，HIV-1蛋白的合成以时间剂量依赖的方式被抑制。高水平的2A蛋白酶表达在感染的前24小时内严重抑制HIV-1蛋白的合成，从而抑制病毒的产生和感染性。中等至较低水平的2A蛋白酶表达仅在病毒复制的前48小时内引起病毒蛋白合成的抑制。在此期间之后，蛋白质合成和病毒释放均恢复至对照水平。然而，病毒子代的感染性仍被部分抑制。这些结果表明，mRNA翻译起始的两种机制有助于HIV-1蛋白的合成;在病毒复制的前24-48小时，HIV-1蛋白的合成强烈依赖于Cap起始，而在随后的时间点，IRES驱动的翻译起始足以产生大量的病毒颗粒。
The 30 different species of mRNAs synthesized during the HIV-1 replication cycle are all capped and polyadenilated. Internal ribosome entry sites have been recognized in the 5′ untranslated region of some mRNA species of HIV-1, which would contribute to an alternative mechanism of initiation of mRNA translation. However, the Cap-dependent translation is assumed to be the main mechanism driving the initiation of HIV-1 protein synthesis. In this work, we describe a cell system in which lower to higher levels of transient expression of the poliovirus 2A protease strongly inhibited cellular Cap-dependent translation with no toxic effect to the cells during a 72-hour time frame. In this system, the synthesis of HIV-1 proteins was inhibited in a temporal dose-dependent way. Higher levels of 2A protease expression severely inhibited HIV-1 protein synthesis during the first 24 hours of infection consequently inhibiting viral production and infectivity. Intermediate to lower levels of 2A Protease expression caused the inhibition of viral protein synthesis only during the first 48 hours of viral replication. After this period both protein synthesis and viral release were recovered to the control levels. However, the infectivity of viral progeny was still partially inhibited. These results indicate that two mechanisms of mRNA translation initiation contribute to the synthesis of HIV-1 proteins; during the first 24–48 hours of viral replication HIV-1 protein synthesis is strongly dependent on Cap-initiation, while at later time points IRES-driven translation initiation is sufficient to produce high amounts of viral particles.
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