G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to Raltegravir whereas Y143C does not
G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to Raltegravir whereas Y143C does not
复制标题
DOI：
10.1186/1742-4690-8-68
复制
发表时间：
2011-08-19
期刊：
影响因子：
3.3
通讯作者：
Mouscadet, Jean-Francois
中科院分区：
文献类型：
--
作者：
Ni, Xiao-Ju;Delelis, Olivier;Mouscadet, Jean-Francois
背景：HIV-2在西非流行，并已蔓延到整个欧洲。然而，HIV-2感染者的替代方案比HIV-1感染者的替代方案更为有限。雷特格韦是一种整合酶抑制剂，对野生型HIV-2有活性，对这种药物的敏感性与HIV-1相似，因此是治疗HIV-2感染患者的一种有希望的选择。最近的研究表明，HIV-2对雷特格韦的耐药性涉及三种耐药突变之一，即N155 H、Q148 R/H和Y143 C，这些突变先前被确定为HIV-1整合酶编码序列中的耐药决定因素。HIV-1 IN对携带这些突变的突变酶的耐药性已在体外得到证实，但对HIV-2尚未得到这种证实。结果：从10例HIV-2感染患者的血浆样品中扩增出整合酶编码序列，其中3例患者在病毒学失败时未接受过RAL治疗，7例患者在病毒学失败时接受了RAL治疗。克隆了耐药菌株的基因组，并鉴定了N155 H、G140 S/Q148 R和Y143 C三种突变模式。对从临床分离株扩增或通过诱变获得的整合酶的敏感性的研究表明，位置155和148处的突变使整合酶对RAL具有抗性。G140 S突变几乎不产生耐药性，但弥补了Q148 R突变引起的催化缺陷。相反，除非E92 Q也存在，否则单独的Y143 C不赋予对RAL的抗性。结论：本研究证实HIV-2对RAL的耐药是由N155 H、G140 S/Q148 R或E92 Q/Y143 C突变引起的。N155 H和G140 S/Q148 R突变对HIV-1和HIV-2的耐药性有相似的贡献，但Y143 C不足以解释携带该突变的HIV-2基因组的耐药性。对于Y143 C在体外赋予耐药性，它必须伴随E92 Q，因此E92 Q在HIV-2背景下比在HIV-1背景下发挥更重要的作用。最后，Y143 C突变抵消了N155 H突变所赋予的耐药性，这可能是由于在单个基因组中没有检测到这些突变的原因。
Background: HIV-2 is endemic in West Africa and has spread throughout Europe. However, the alternatives for HIV-2-infected patients are more limited than for HIV-1. Raltegravir, an integrase inhibitor, is active against wild-type HIV-2, with a susceptibility to this drug similar to that of HIV-1, and is therefore a promising option for use in the treatment of HIV-2-infected patients. Recent studies have shown that HIV-2 resistance to raltegravir involves one of three resistance mutations, N155H, Q148R/H and Y143C, previously identified as resistance determinants in the HIV-1 integrase coding sequence. The resistance of HIV-1 IN has been confirmed in vitro for mutated enzymes harboring these mutations, but no such confirmation has yet been obtained for HIV-2.Results: The integrase coding sequence was amplified from plasma samples collected from ten patients infected with HIV-2 viruses, of whom three RAL-naive and seven on RAL-based treatment at the time of virological failure. The genomes of the resistant strains were cloned and three patterns involving N155H, G140S/Q148R or Y143C mutations were identified. Study of the susceptibility of integrases, either amplified from clinical isolates or obtained by mutagenesis demonstrated that mutations at positions 155 and 148 render the integrase resistant to RAL. The G140S mutation conferred little resistance, but compensated for the catalytic defect due to the Q148R mutation. Conversely, Y143C alone did not confer resistance to RAL unless E92Q is also present. Furthermore, the introduction of the Y143C mutation into the N155H resistant background decreased the resistance level of enzymes containing the N155H mutation.Conclusion: This study confirms that HIV-2 resistance to RAL is due to the N155H, G140S/Q148R or E92Q/Y143C mutations. The N155H and G140S/Q148R mutations make similar contributions to resistance in both HIV-1 and HIV-2, but Y143C is not sufficient to account for the resistance of HIV-2 genomes harboring this mutation. For Y143C to confer resistance in vitro, it must be accompanied by E92Q, which therefore plays a more important role in the HIV-2 context than in the HIV-1 context. Finally, the Y143C mutation counteracts the resistance conferred by the N155H mutation, probably accounting for the lack of detection of these mutations together in a single genome.