Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication.
Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication.
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DOI：
10.1186/s12977-017-0374-1
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发表时间：
2017-11-09
期刊：
影响因子：
3.3
通讯作者：
Swanson CM
中科院分区：
文献类型：
--
作者：
Antzin-Anduetza I;Mahiet C;Granger LA;Odendall C;Swanson CM
人类免疫缺陷病毒1型(HIV-1)结构蛋白Gag是形成病毒颗粒的必要条件和充分条件。除了编码Gag的氨基酸序列外，潜在的RNA序列还可以编码病毒复制所必需的顺式作用元件或核苷酸偏向。此外，抑制病毒复制的RNA序列可以在GAG中被抑制。然而，促进或抑制HIV-1复制的RNA元件和核苷酸偏向的功能相关性仍然知之甚少。为了确定GAG中的RNA序列是否控制HIV-1的复制，对基质(MA)区域进行了密码子修改，允许RNA序列在不影响蛋白质序列的情况下发生改变。GAG中22-261或22-378位核苷酸的密码子修饰通过降低基因组RNA(GRNA)丰度、gRNA稳定性、GAG表达、病毒粒子产量和感染性来抑制病毒复制。比较这些点突变和相同区域的缺失的效果，发现突变抑制了传染性病毒的产生，而缺失则没有。这表明密码子修饰引入了抑制序列。在HIV-1中，CpG二核苷酸的频率远远低于预期，密码子修改导致CpG丰度大幅增加。为了确定它们是否是抑制HIV-1复制所必需的，引入CpG二核苷酸的密码子被突变回野生型密码子，恢复了有效的Gag表达和感染性病毒粒子的产生。为了确定它们是否足以抑制病毒复制，在没有其他变化的情况下将CpG二核苷酸插入到GAG中。CpG二核苷酸含量的增加降低了HIV-1的传染性和病毒复制。HIV-1RNA序列含有低丰度的CpG二核苷酸。增加CpG二核苷酸的丰度可以抑制病毒生命周期的多个步骤，为为什么CpG二核苷酸在HIV-1中被抑制提供了一个功能上的解释。本文的在线版本(10.1186/s12977-0170374-1)包含补充材料，可供授权用户使用。
The human immunodeficiency virus type 1 (HIV-1) structural protein Gag is necessary and sufficient to form viral particles. In addition to encoding the amino acid sequence for Gag, the underlying RNA sequence could encode cis-acting elements or nucleotide biases that are necessary for viral replication. Furthermore, RNA sequences that inhibit viral replication could be suppressed in gag. However, the functional relevance of RNA elements and nucleotide biases that promote or repress HIV-1 replication remain poorly understood. To characterize if the RNA sequence in gag controls HIV-1 replication, the matrix (MA) region was codon modified, allowing the RNA sequence to be altered without affecting the protein sequence. Codon modification of nucleotides (nt) 22-261 or 22-378 in gag inhibited viral replication by decreasing genomic RNA (gRNA) abundance, gRNA stability, Gag expression, virion production and infectivity. Comparing the effect of these point mutations to deletions of the same region revealed that the mutations inhibited infectious virus production while the deletions did not. This demonstrated that codon modification introduced inhibitory sequences. There is a much lower than expected frequency of CpG dinucleotides in HIV-1 and codon modification introduced a substantial increase in CpG abundance. To determine if they are necessary for inhibition of HIV-1 replication, codons introducing CpG dinucleotides were mutated back to the wild type codon, which restored efficient Gag expression and infectious virion production. To determine if they are sufficient to inhibit viral replication, CpG dinucleotides were inserted into gag in the absence of other changes. The increased CpG dinucleotide content decreased HIV-1 infectivity and viral replication. The HIV-1 RNA sequence contains low abundance of CpG dinucleotides. Increasing the abundance of CpG dinucleotides inhibits multiple steps of the viral life cycle, providing a functional explanation for why CpG dinucleotides are suppressed in HIV-1. The online version of this article (10.1186/s12977-017-0374-1) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.tig.2017.02.001
发表时间：
2017-04
期刊：
Trends in genetics : TIG
影响因子：
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