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首页> 外文期刊>Retrovirology >A common mechanism of clinical HIV-1 resistance to the CCR5 antagonist maraviroc despite divergent resistance levels and lack of common gp120 resistance mutations
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A common mechanism of clinical HIV-1 resistance to the CCR5 antagonist maraviroc despite divergent resistance levels and lack of common gp120 resistance mutations

机译：尽管耐药水平不同且缺乏常见的gp120耐药突变，但临床HIV-1对CCR5拮抗剂maraviroc耐药的常见机制

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Background The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize CCR5. The mechanisms of HIV-1 resistance to MVC, the only CCR5 antagonist licensed for clinical use are poorly understood, with insights into MVC resistance almost exclusively limited to knowledge obtained from in vitro studies or from studies of resistance to other CCR5 antagonists. To more precisely understand mechanisms of resistance to MVC in vivo, we characterized Envs isolated from 2 subjects who experienced virologic failure on MVC. Results Envs were cloned from subjects 17 and 24 before commencement of MVC (17-Sens and 24-Sens) and after virologic failure (17-Res and 24-Res). The Envs cloned during virologic failure showed broad divergence in resistance levels, with 17-Res Env exhibiting a relatively high maximal percent inhibition (MPI) of ~90% in NP2-CD4/CCR5 cells and peripheral blood mononuclear cells (PBMC), and 24-Res Env exhibiting a very low MPI of ~0 to 12% in both cell types, indicating relatively “weak” and “strong” resistance, respectively. Resistance mutations were strain-specific and mapped to the gp120 V3 loop. Affinity profiling by the 293-Affinofile assay and mathematical modeling using VERSA (Viral Entry Receptor Sensitivity Analysis) metrics revealed that 17-Res and 24-Res Envs engaged MVC-bound CCR5 inefficiently or very efficiently, respectively. Despite highly divergent phenotypes, and a lack of common gp120 resistance mutations, both resistant Envs exhibited an almost superimposable pattern of dramatically increased reliance on sulfated tyrosine residues in the CCR5 N-terminus, and on histidine residues in the CCR5 ECLs. This altered mechanism of CCR5 engagement rendered both the resistant Envs susceptible to neutralization by a sulfated peptide fragment of the CCR5 N-terminus. Conclusions Clinical resistance to MVC may involve divergent Env phenotypes and different genetic alterations in gp120, but the molecular mechanism of resistance of the Envs studied here appears to be related. The increased reliance on sulfated CCR5 N-terminus residues suggests a new avenue to block HIV-1 entry by CCR5 N-terminus sulfopeptidomimetic drugs.
机译：背景技术CCR5拮抗剂maraviroc（MVC）通过改变CCR5细胞外环（ECL）来抑制1型人类免疫缺陷病毒（HIV-1）的进入，从而使gp120包膜糖蛋白（Env）不再识别CCR5。 HIV-1对MVC的抗药性的机制知之甚少，对MVC的抗药性的见识几乎仅限于从体外研究或对其他CCR5拮抗剂的抗药性研究中获得的知识。为了更准确地了解体内对MVC的抗性机制，我们对从2名经历MVC病毒学衰竭的受试者中分离的Envs进行了表征。结果在MVC开始前（17-Sens和24-Sens）和病毒学衰竭（17-Res和24-Res）后，从受试者17和24中克隆了Env。在病毒学失败期间克隆的Envs在耐药水平上表现出很大的差异，其中17-Res Env在NP2-CD4 / CCR5细胞和外周血单核细胞（PBMC）中表现出相对较高的最大抑制百分比（MPI），约为90％。 -Res Env在两种细胞类型中均表现出非常低的MPI，约〜0％至12％，分别表示相对“弱”和“强”抗性。抗性突变是菌株特异性的，并定位到gp120 V3环。通过293-Affinofile分析进行亲和谱分析以及使用VERSA（病毒进入受体敏感性分析）指标进行数学建模，结果表明17-Res和24-Res Envs分别低效或非常有效地结合了MVC结合的CCR5。尽管表型高度不同，并且缺乏常见的gp120抗性突变，但两种抗性Env都表现出几乎重叠的模式，其显着增加了CCR5 N端硫酸盐酪氨酸残基和CCR5 ECL中组氨酸残基的依赖性。 CCR5接合机制的这种改变使两个耐药的Envs易于被CCR5 N末端的硫酸化肽片段中和。结论对MVC的临床耐药性可能涉及gp120中不同的Env表型和不同的遗传改变，但此处研究的Envs耐药的分子机制似乎是相关的。对硫酸化的CCR5 N-末端残基的依赖性增加，表明一条新的途径可以阻止CCR5 N-末端磺肽模拟药物使HIV-1进入。

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