Nikita Reddy, Maria Papathanasopoulos, Kim Steegen, Adriaan Erasmus Basson
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引用次数: 0
摘要
多拉韦林(DOR)是一种非核苷类逆转录酶抑制剂(NNRTI),对一些 NNRTI 耐药突变体有效。虽然 DOR 对 HIV-1 B 亚型的耐药性突变已经确定,但对非 B 亚型的耐药性突变还不太清楚。本研究调查了 HIV-1 C 亚型中普遍存在的 NNRTI 耐药突变对 DOR 的敏感性。将单一或组合突变引入复制缺陷假病毒,并在体外评估其对 DOR 的敏感性。单一的 V106M 和 Y188L 突变会导致高水平的耐药性,而其他突变对 DOR 的敏感性影响不大。我们观察到体外检测结果与斯坦福艾滋病毒数据库预测的敏感性之间存在一致性。然而,F227L 突变被预测为会导致高水平的 DOR 抗性,但在体外却是易感的。含有 K103N、V106M 或 Y188L 的突变组合会导致高水平的耐药性,这与预测结果一致。在依非韦伦或奈韦拉平一线治疗方案失败的患者中,经常可以观察到这些突变。然而,正如我们在数据库中观察到的那样,在使用蛋白酶抑制剂二线疗法失败的患者中也能观察到这些突变。因此,在开始使用基于 DOR 的治疗前,对那些曾接受过依非韦伦或奈韦拉平治疗的患者进行基因型耐药性检测至关重要。
K103N, V106M and Y188L Significantly Reduce HIV-1 Subtype C Phenotypic Susceptibility to Doravirine.
Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI-resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz- or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to the initiation of DOR-based treatment for those previously exposed to efavirenz or nevirapine.
期刊介绍:
Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.