Institute of Virology, University of Cologne, Fürst-Pückler Str. 56, 50935 Cologne, Germany.
J Antimicrob Chemother. 2010 Jul;65(7):1472-6. doi: 10.1093/jac/dkq129. Epub 2010 Apr 29.
To analyse HIV Gag cleavage site (CS) and non-CS mutations in HIV non-B isolates from patients failing antiretroviral therapy.
Twenty-one HIV isolates were obtained from patients infected with HIV subtype G during an outbreak in Russia 20 years ago. Most patients were failing antiretroviral therapy when genotyping was performed.
HIV Gag CS mutations accumulated in protease inhibitor (PI)-resistant HIV isolates and were correlated with the presence of three or more PI resistance mutations. Only 1 of 11 HIV isolates carrying major protease mutations did not harbour treatment-associated CS mutations. Natural polymorphism 453T, often found in HIV non-B subtypes, seems to favour the selection of CS mutation 453I rather than treatment-associated CS mutation 453L. Resistance-associated non-CS mutations (123E and 200I) were also observed in PI-resistant clinical isolates. Non-CS mutations in the frameshift-regulating site, which controls the synthesis of Gag-Pol, did not affect frameshift efficiency in dual luciferase assays. Of note, one of four HIV isolates from patients failing PI therapies without protease mutations harboured Gag mutations associated with PI resistance (123E and 436R) and reverse transcriptase inhibitor mutations conferring resistance to the backbone drug.
HIV Gag CS mutations commonly occurred in HIV isolates from patients failing PI therapies and natural polymorphisms at the same position influence their emergence. Non-CS mutations previously associated with PI resistance were also observed in clinical isolates. Gag mutations might indicate the evolution of PI resistance even in the absence of protease mutations.
分析在抗逆转录病毒治疗失败的患者中分离到的非 B 型 HIV 非结构蛋白 Gag 切割位点（CS）和非 CS 突变。
21 株 HIV 分离株是在 20 年前俄罗斯发生 HIV 爆发期间从感染 HIV G 亚型的患者中获得的。进行基因分型时，大多数患者都在接受抗逆转录病毒治疗。
在对蛋白酶抑制剂（PI）耐药的 HIV 中积累了 HIV Gag CS 突变，且与存在三种或更多 PI 耐药突变相关。在携带主要蛋白酶突变的 11 株 HIV 分离株中，只有 1 株未携带治疗相关 CS 突变。在非 B 亚型 HIV 中经常发现的自然多态性 453T 似乎有利于选择 CS 突变 453I，而不是治疗相关的 CS 突变 453L。在 PI 耐药临床分离株中还观察到非 CS 突变 123E 和 200I。在控制 Gag-Pol 合成的框架移位调节位点的非 CS 突变不会影响双荧光素酶测定中的框架移位效率。值得注意的是，在没有蛋白酶突变而抗 PI 治疗失败的患者中分离的 4 株 HIV 分离株中有 1 株携带与 PI 耐药相关的 Gag 突变（123E 和 436R）以及与骨干药物耐药相关的逆转录酶抑制剂突变。
HIV Gag CS 突变常见于抗 PI 治疗失败的患者中分离到的 HIV 分离株中，且相同位置的自然多态性影响其出现。先前与 PI 耐药相关的非 CS 突变也在临床分离株中观察到。即使在缺乏蛋白酶突变的情况下，Gag 突变也可能表明 PI 耐药的进化。
