The HIV-1 Rev/RRE system is required for HIV-1 5' UTR cis elements to augment encapsidation of heterologous RNA into HIV-1 viral particles.
The HIV-1 Rev/RRE system is required for HIV-1 5' UTR cis elements to augment encapsidation of heterologous RNA into HIV-1 viral particles.
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DOI：
10.1186/1742-4690-8-51
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发表时间：
2011-06-24
期刊：
影响因子：
3.3
通讯作者：
Kafri T
中科院分区：
文献类型：
--
作者：
Cockrell AS;van Praag H;Santistevan N;Ma H;Kafri T
HIV-1基因组RNA（gRNA）的折叠过程受许多病毒编码组分的控制，最值得注意的是典型包装信号（conventional packaging signal，gRNA）中的Gag蛋白和gRNA顺式元件。也涉及到5'非翻译区（UTR）的R、U 5和PBS（引物结合位点）中的顺式决定簇。尽管通常与HIV-1 RNA的核输出相关，但Rev/RRE在胞苷化过程中的作用正在迅速发展。这些顺式和反式病毒组分所表现出的多效性效应可能混淆了检查它们在其先天病毒背景下对RNA掺入HIV-1病毒颗粒的独立和组合影响的能力。我们在异源鼠白血病病毒（MLV）载体RNA的背景下系统地重建了HIV-1包装系统，以阐明Rev/RRE系统是实现有效和特异性包裹HIV-1病毒颗粒的核心机制。我们首次证明Rev/RRE系统可以独立于来自5' UTR的所有顺式元件（R、U 5、PBS和p53）而增强RNA的双核苷化。在不存在Rev/RRE系统的情况下，所有5' UTR顺式元件的掺入不增强RNA的折叠。事实上，我们证明，Rev/RRE系统是需要特定的和有效的adhesidation通常与规范的包装信号。Rev/RRE介导的双糖苷化机制不是普遍现象，因为Rev/RRE系统和5' UTR顺式元件的组合不增强双糖苷化成MLV衍生的病毒颗粒。最后，我们表明，异源MLV RNA符合通常与HIV-1病毒颗粒相关的转导特性，包括非分裂细胞（即小鼠神经元）的体内转导;然而，cDNA形式主要是1-LTR环形式的附加体。以异源RNA被折叠成HIV-1病毒颗粒为前提，我们的发现将功能性HIV-1包装系统定义为包含5' UTR顺式元件Gag和Rev/RRE系统，其中需要Rev/RRE系统来使RNA服从Gag和用于随后折叠的规范包装信号之间的随后相互作用。
The process of HIV-1 genomic RNA (gRNA) encapsidation is governed by a number of viral encoded components, most notably the Gag protein and gRNA cis elements in the canonical packaging signal (ψ). Also implicated in encapsidation are cis determinants in the R, U5, and PBS (primer binding site) from the 5' untranslated region (UTR). Although conventionally associated with nuclear export of HIV-1 RNA, there is a burgeoning role for the Rev/RRE in the encapsidation process. Pleiotropic effects exhibited by these cis and trans viral components may confound the ability to examine their independent, and combined, impact on encapsidation of RNA into HIV-1 viral particles in their innate viral context. We systematically reconstructed the HIV-1 packaging system in the context of a heterologous murine leukemia virus (MLV) vector RNA to elucidate a mechanism in which the Rev/RRE system is central to achieving efficient and specific encapsidation into HIV-1 viral particles. We show for the first time that the Rev/RRE system can augment RNA encapsidation independent of all cis elements from the 5' UTR (R, U5, PBS, and ψ). Incorporation of all the 5' UTR cis elements did not enhance RNA encapsidation in the absence of the Rev/RRE system. In fact, we demonstrate that the Rev/RRE system is required for specific and efficient encapsidation commonly associated with the canonical packaging signal. The mechanism of Rev/RRE-mediated encapsidation is not a general phenomenon, since the combination of the Rev/RRE system and 5' UTR cis elements did not enhance encapsidation into MLV-derived viral particles. Lastly, we show that heterologous MLV RNAs conform to transduction properties commonly associated with HIV-1 viral particles, including in vivo transduction of non-dividing cells (i.e. mouse neurons); however, the cDNA forms are episomes predominantly in the 1-LTR circle form. Premised on encapsidation of a heterologous RNA into HIV-1 viral particles, our findings define a functional HIV-1 packaging system as comprising the 5' UTR cis elements, Gag, and the Rev/RRE system, in which the Rev/RRE system is required to make the RNA amenable to the ensuing interaction between Gag and the canonical packaging signal for subsequent encapsidation.
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