VSV-G pseudotyping rescues HIV-1 CA mutations that impair core assembly or stability.
VSV-G pseudotyping rescues HIV-1 CA mutations that impair core assembly or stability.
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DOI：
10.1186/1742-4690-5-57
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发表时间：
2008-07-07
期刊：
影响因子：
3.3
通讯作者：
Briant L
中科院分区：
文献类型：
--
作者：
Brun S;Solignat M;Gay B;Bernard E;Chaloin L;Fenard D;Devaux C;Chazal N;Briant L
HIV-1早期复制的机制仍有待阐明。最近报道，病毒核心以组装颗粒的形式存在于感染细胞的细胞质中，产生逆转录复合体，负责合成前病毒DNA并将其运输到细胞核。大量研究表明，HIV-1基因组到前病毒DNA的逆转录密切依赖于衣壳(CA)蛋白正确组装成表现出适当稳定性的成熟核心。在早期复制步骤中，核心的结构特性对功能的影响尚未确定。在这里，我们表明，在CA中携带S149A和S178A突变的HIV-1突变株，当与水泡性口炎病毒包膜糖蛋白进行假型时，可以有效地恢复其感染性，该蛋白通过内吞途径解决突变核心，而不是通过在质膜上融合。对这些突变破坏病毒感染性的机制进行了研究。S149A和S178A突变体不能完成逆转录和/或产生2-LTRDNA。病毒颗粒的形态分析和分离核心的体外去包被分析表明，S149A和S178A突变体的感染性缺陷分别是由于病毒核心组装和稳定性的破坏造成的。与这些结果一致的是，两个突变体都未能饱和TRIM-抗病毒限制活性。S149A和S178A突变在核心组装和稳定性水平上产生的缺陷对病毒核蛋白复合体进入靶细胞的方式敏感。通过内吞途径解决CA突变体可能会补偿核心组装或稳定性受损后在反转录/核进口水平上产生的缺陷。
The machinery of early HIV-1 replication still remains to be elucidated. Recently the viral core was reported to persist in the infected cell cytoplasm as an assembled particle, giving rise to the reverse transcription complex responsible for the synthesis of proviral DNA and its transport to the nucleus. Numerous studies have demonstrated that reverse transcription of the HIV-1 genome into proviral DNA is tightly dependent upon proper assembly of the capsid (CA) protein into mature cores that display appropriate stability. The functional impact of structural properties of the core in early replicative steps has yet to be determined. Here, we show that infectivity of HIV-1 mutants bearing S149A and S178A mutations in CA can be efficiently restored when pseudotyped with vesicular stomatitis virus envelope glycoprotein, that addresses the mutant cores through the endocytic pathway rather than by fusion at the plasma membrane. The mechanisms by which these mutations disrupt virus infectivity were investigated. S149A and S178A mutants were unable to complete reverse transcription and/or produce 2-LTR DNA. Morphological analysis of viral particles and in vitro uncoating assays of isolated cores demonstrated that infectivity defects resulted from disruption of the viral core assembly and stability for S149A and S178A mutants, respectively. Consistent with these results, both mutants failed to saturate TRIM-antiviral restriction activity. Defects generated at the level of core assembly and stability by S149A and S178A mutations are sensitive to the way of delivery of viral nucleoprotein complexes into the target cell. Addressing CA mutants through the endocytic pathway may compensate for defects generated at the reverse transcription/nuclear import level subsequent to impairment of core assembly or stability.
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影响因子：
11.4
作者：
Jacqué, JM;Mann, A;Stevenson, M
通讯作者：
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