Division of Infectious Diseases, Brown University, Providence, RI, USA.
Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya.
J Int AIDS Soc. 2017 Nov;20(3). doi: 10.1002/jia2.25024.
Failure of protease-inhibitor (PI)-based second-line antiretroviral therapy (ART) with medication adherence but no protease drug resistance mutations (DRMs) is not well understood. This study investigated the involvement of gp41 and gag as alternative mechanisms, not captured by conventional resistance testing and particularly relevant in resource-limited settings where third-line ART is limited.
We evaluated gp41 and gag for unique amino acids in seven subtype A infected Kenyans failing second-line therapy with no PI resistance yet detectable lopinavir (query dataset), compared to seven similar-setting patients with PI resistance or undetectable lopinavir and 69 publically available subtype A Kenyan whole-genomes sequences.
Three gp41 (607T, 641L, 721I) and four gag (124S, 143V, 339P, 357S) amino acids were significantly more frequent in the query dataset compared to the other datasets, with significantly high co-occurrence.
The genotypic analysis of a unique group of HIV-1 subtype A infected patients, identified seven amino acids that could potentially contribute to a multi-gene mechanism of PI-based ART failure in the absence of PI DR mutations.
尽管药物依从性良好，但在蛋白酶抑制剂（PI）为基础的二线抗逆转录病毒治疗（ART）中出现耐药失败，且不存在蛋白酶耐药突变（DRMs）的情况，目前尚未得到很好的理解。本研究旨在探讨 gp41 和 gag 作为替代机制的参与情况，这些机制无法通过常规耐药检测捕捉到，特别是在资源有限的环境中，三线 ART 受到限制，这些替代机制显得尤为重要。
我们评估了七个感染 HIV-1 亚型 A 的肯尼亚患者在二线治疗中出现耐药失败但未检测到 PI 耐药突变（查询数据集）的 gp41 和 gag 的独特氨基酸，与七个具有 PI 耐药或未检测到洛匹那韦的类似设定患者以及 69 个公开的肯尼亚 HIV-1 亚型 A 全基因组序列进行比较。
与其他数据集相比，查询数据集中的三个 gp41（607T、641L、721I）和四个 gag（124S、143V、339P、357S）氨基酸的出现频率明显更高，且具有明显的高共现性。
对一组独特的 HIV-1 亚型 A 感染患者进行基因分析，确定了七个可能有助于在不存在 PI 耐药突变的情况下，通过多基因机制导致基于 PI 的 ART 治疗失败的氨基酸。
