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首页> 外文期刊>AIDS Research and Human Retroviruses >Analysis of Clinical HIV-1 Strains with Resistance to Maraviroc Reveals Strain-Specific Resistance Mutations, Variable Degrees of Resistance, and Minimal Cross-Resistance to Other CCR5 Antagonists
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Analysis of Clinical HIV-1 Strains with Resistance to Maraviroc Reveals Strain-Specific Resistance Mutations, Variable Degrees of Resistance, and Minimal Cross-Resistance to Other CCR5 Antagonists

机译：临床HIV-1株的抗性抗马拉西病株揭示了菌株特异性的抗性突变，可变性程度的抗性，以及对其他CCR5拮抗剂的最小交叉抗性

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摘要

Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n=77) from plasma of pretreatment (n=36) and treatment failure (n=41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.
机译：Maraviroc（MVC）是人免疫缺陷病毒类型1（HIV-1）进入的颠覆抑制剂，是唯一用作抗HIV-1治疗的CCR5拮抗剂。它通过改变CCR5细胞外环的构象，通过HIV-1封套（env）糖蛋白来透明地呈现CCR5。本研究旨在了解HIV-1感染患者MVC抗性发展的机制。为此，我们从八个受试者获得纵向血浆样本，该血浆样本经历了在表型验证的CCR5-热带MVC抗性的治疗失败。然后，我们从预处理的血浆（n = 36）和治疗失败（n = 41）样品中克隆和表征HIV-1 ENVS（n = 77）。我们的结果表明，通过减少抑制Env-伪型病毒的最大抑制的抑制测量的MVC电阻幅度的变化，其与具有相似水平的CCR5表达水平的细胞更明显。 MVC电阻的氨基酸决定簇定位于V3 env区域并具有菌株特异性。我们还观察到MVC抗性菌株对其他CCR5拮抗剂的最小交叉抗性。我们得出结论，293辅助细胞对通过CCR5依赖性的机制检测和测量MVC抗性的高敏感性，但是依赖于CCR5表达水平。抗性突变的菌株特异性表明，基于序列的诊断和预测需要比简单的位置得分更复杂，以便在采用MVC的受试者中进行抗性。最后，最小的横抗水平表明，识别MVC改性形式的CCR5不一定导致识别其他拮抗剂改性形式的CCR5。

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