Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Paris 06, INSERM U943, Paris, France.
J Antimicrob Chemother. 2011 Dec;66(12):2827-30. doi: 10.1093/jac/dkr389. Epub 2011 Sep 19.
Most of the previous studies that explored the molecular basis of raltegravir resistance were conducted studying the HIV-1 B subtype. It has been shown that the CRF02_AG subtype in relation to its natural integrase (IN) sequence could develop different genetic pathways associated with raltegravir resistance. The aim of this study was to explore resistance pathways preferably used by CRF02_AG viruses compared with subtype B.
Twenty-five HIV-1 CRF02_AG-infected patients failing a raltegravir-containing regimen were studied. IN gene sequences were examined for the presence of previously described IN inhibitor (raltegravir, elvitegravir, dolutegravir and MK-2048) resistance mutations at 20 amino acid positions.
Among the 25 studied patients, 7 showed viruses harbouring major raltegravir resistance mutations mainly associated with the 155 genetic pathways and 18 showed viruses harbouring none of them; however, for 1 patient, we found a 118R mutation, associated with MK-2048 in vitro resistance, in a 74M background. For this patient, the phenotypic analysis showed that addition of only the G118R mutation conferred a high level of resistance to raltegravir (fold change = 25.5) and elvitegravir (fold change = 9.2).
This study confirmed that mutation pathways for raltegravir resistance could be different between the two subtypes CRF02_AG and B with a preferential use of the 155 mutation in non-B subtypes. A new genetic pathway associated with raltegravir resistance, including the 118R mutation, has also been identified. This new genetic pathway, never described in subtype B, should be further evaluated for phenotypic susceptibility to dolutegravir and MK-2048.
之前探索拉替拉韦耐药分子基础的大多数研究都是针对 HIV-1 B 亚型进行的。研究表明，相对于其天然整合酶（IN）序列，CRF02_AG 亚型可能会发展出与拉替拉韦耐药相关的不同遗传途径。本研究旨在探索 CRF02_AG 病毒比 B 亚型更倾向使用的耐药途径。
研究了 25 例因拉替拉韦含药方案失败而感染 HIV-1 CRF02_AG 的患者。在 20 个氨基酸位置检测 IN 基因序列中是否存在先前描述的 IN 抑制剂（拉替拉韦、艾维雷格、多替拉韦和 MK-2048）耐药突变。
在 25 例研究患者中，7 例患者的病毒携带主要与 155 遗传途径相关的拉替拉韦耐药突变，18 例患者的病毒均未携带这些突变；然而，对于 1 例患者，我们发现了一个 118R 突变，该突变与体外 MK-2048 耐药相关，在 74M 背景下。对于该患者，表型分析表明，仅添加 G118R 突变即可使拉替拉韦（耐药倍数=25.5）和艾维雷格（耐药倍数=9.2）的耐药水平显著升高。
本研究证实，拉替拉韦耐药的突变途径在 CRF02_AG 和 B 两个亚型之间可能不同，非 B 亚型更倾向于使用 155 突变。还确定了一种与拉替拉韦耐药相关的新遗传途径，包括 118R 突变。这种在 B 亚型中从未描述过的新遗传途径，应进一步评估其对多替拉韦和 MK-2048 的表型敏感性。
