UMR 943, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Virologie, Paris France.
AIDS. 2010 Sep 24;24(15):2313-21. doi: 10.1097/QAD.0b013e32833e515a.
The HIV-1 Vif protein counteracts the antiviral activity of the cytidine deaminases APOBEC3G and APOBEC3F. Natural variation in Vif may result in reduced efficacy against APOBEC3 proteins and in increased HIV-1 diversity. We speculated that this mechanism could facilitate viral escape from certain antiretroviral drugs.
We analyzed the protease, reverse transcriptase and Vif sequences of viruses from plasma obtained from 92 HIV-1-infected individuals failing antiretroviral treatment and 65 antiretroviral-naive patients. Mutation K22H in Vif was more frequent in patients failing to antiretroviral compared to antiretroviral-naive patients. In-vitro experiments showed that mutant K22H failed to completely neutralize APOBEC3G. Upon infection of MT-2 cells, most of the K22H proviral clones encoded increased numbers of G-to-A mutations. Among these mutations, the lamivudine drug-resistance-associated mutation M184I in reverse transcriptase was detected in 25% of clones in the absence of any lamivudine exposure. In our population, among pretreated patients, 72% of K22H viruses versus 42% in WT K22 viruses harbored at least two drug-resistance-associated mutations in a GA/GG dinucleotide context. More specifically, K22H viruses harbored significantly more G16E and M36I in protease than in those isolated from pretreated patients harboring WT K22 viruses.
This study provides evidence that patients experiencing virological failure frequently harbor Vif point mutants (i.e. K22H). Such Vif alleles lose their ability to counteract APOBEC3 proteins, leading to an increase of G-to-A viral mutations that can facilitate the emergence of some antiretroviral resistance mutations.
HIV-1 Vif 蛋白可拮抗抗病毒因子 APOBEC3G 和 APOBEC3F 的活性。Vif 的自然变异可能导致其针对 APOBEC3 蛋白的功效降低，并增加 HIV-1 的多样性。我们推测，这种机制可以促进病毒逃避某些抗逆转录病毒药物。
我们分析了 92 名接受抗逆转录病毒治疗失败的 HIV-1 感染者和 65 名未接受抗逆转录病毒治疗的患者血浆中病毒的蛋白酶、逆转录酶和 Vif 序列。与未接受抗逆转录病毒治疗的患者相比，Vif 中的 K22H 突变在抗逆转录病毒治疗失败的患者中更为常见。体外实验表明，突变的 K22H 不能完全中和 APOBEC3G。在 MT-2 细胞感染中，大多数 K22H 前病毒克隆编码的 G 至 A 突变数量增加。在这些突变中，在没有任何拉米夫定暴露的情况下，逆转录酶中与拉米夫定耐药相关的 M184I 突变在 25%的克隆中被检测到。在我们的人群中，在接受过治疗的患者中，72%的 K22H 病毒比 WT K22 病毒携带至少两个在 GA/GG 二核苷酸环境中与药物耐药相关的突变。更具体地说，K22H 病毒在蛋白酶中携带的 G16E 和 M36I 明显多于从携带 WT K22 病毒的接受过治疗的患者中分离出的病毒。
本研究提供了证据表明，经历病毒学失败的患者经常携带 Vif 点突变（即 K22H）。这种 Vif 等位基因丧失了拮抗 APOBEC3 蛋白的能力，导致 G 至 A 病毒突变增加，从而促进了一些抗逆转录病毒耐药突变的出现。
