Lifesequencing SL, Paterna, Spain.
Universidad Catolica de Valencia, Valencia, Spain.
Sci Rep. 2017 Jun 16;7(1):3717. doi: 10.1038/s41598-017-03260-4.
Despite the major role of Gag in establishing resistance of HIV-1 to protease inhibitors (PIs), very limited data are available on the total contribution of Gag residues to resistance to PIs. To identify in detail Gag residues and structural interfaces associated with the development of HIV-1 resistance to PIs, we traced viral evolution under the pressure of PIs using Gag-protease single genome sequencing and coevolution analysis of protein sequences in 4 patients treated with PIs over a 9-year period. We identified a total of 38 Gag residues correlated with the protease, 32 of which were outside Gag cleavage sites. These residues were distributed in 23 Gag-protease groups of coevolution, with the viral matrix and the capsid represented in 87% and 52% of the groups. In addition, we uncovered the distribution of Gag correlated residues in specific protein surfaces of the inner face of the viral matrix and at the Cyclophilin A binding loop of the capsid. In summary, our findings suggest a tight interdependency between Gag structural proteins and the protease during the development of resistance of HIV-1 to PIs.
尽管 Gag 在建立 HIV-1 对蛋白酶抑制剂（PIs）的耐药性方面起着重要作用，但关于 Gag 残基对 PIs 耐药性的总贡献，数据非常有限。为了详细确定与 HIV-1 对 PIs 耐药性发展相关的 Gag 残基和结构界面，我们使用 Gag-蛋白酶单基因组测序和 4 名接受 PIs 治疗超过 9 年的患者的蛋白质序列共进化分析，追踪了在 PIs 压力下病毒的进化。我们总共鉴定了 38 个与蛋白酶相关的 Gag 残基，其中 32 个位于 Gag 切割位点之外。这些残基分布在 23 个 Gag-蛋白酶共进化组中，其中病毒基质和衣壳分别占 87%和 52%。此外，我们还揭示了 Gag 相关残基在病毒基质内部表面特定蛋白质表面和衣壳环孢素 A 结合环中的分布。总之，我们的研究结果表明，在 HIV-1 对 PIs 的耐药性发展过程中，Gag 结构蛋白与蛋白酶之间存在紧密的相互依存关系。
