Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir
Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir
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DOI：
10.1016/j.antiviral.2005.07.003
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发表时间：
2005-10-01
影响因子：
7.6
通讯作者：
Cordingley, MG
中科院分区：
文献类型：
--
作者：
Doyon, L;Tremblay, S;Cordingley, MG
替普那韦是一种新型的非肽性蛋白酶抑制剂，对多种蛋白酶抑制剂耐药的HIV-1具有广泛的抗病毒活性。然而，对这种抑制剂的耐药性尚未得到很好的描述。HIV在替普那韦存在下传代9个月，以选择具有耐药表型的HIV。对所选变异的特征分析显示，首先被选择的突变是病毒蛋白酶中的L33F和184V，这两个突变加在一起对替普那韦的耐药性不到两倍。在选择实验结束时，病毒在蛋白酶（L10F, I13V, V32I, L33F）中携带了10个突变。M36I、K45I、I54V、A71V、V82L、184V)和CA/SP1 gag切割位点突变对替那韦的敏感性降低了87倍。在体外，替普那韦耐药病毒的复制能力降低，不能通过引入CA/SP1切割位点突变来改善。替普那韦耐药病毒对除沙奎那韦外的其他目前批准的蛋白酶抑制剂显示交叉耐药。这些结果表明，替普那韦耐药表型与蛋白酶的复杂基因型变化有关。抗性需要多种突变的连续积累。(c) 2005 Elsevier B.V.版权所有
Tipranavir is a novel, non-peptidic protease inhibitor, which possesses broad antiviral activity against multiple protease inhibitor-resistant HIV-1. Resistance to this inhibitor however has not yet been well described. HIV was passaged for 9 months in culture in the presence of tipranavir to select HIV with a drug-resistant phenotype. Characterization of the selected variants revealed that the first mutations to be selected were L33F and 184V in the viral protease, mutations which together conferred less than two-fold resistance to tipranavir. At the end of the selection experiments, viruses harbouring 10 mutations in the protease (L10F, I13V, V32I, L33F. M36I, K45I, I54V, A71V, V82L, 184V) as well as a mutation in the CA/SP1 gag cleavage site were selected and showed 87-fold decreased susceptibility to tipranavir. In vitro, tipranavir-resistant viruses had a reduced replicative capacity which could not be improved by the introduction of the CA/SP1 cleavage site mutation. Tipranavir resistant viruses showed cross-resistance to other currently approved protease inhibitors with the exception of saquinavir. These results demonstrate that the tipranavir resistance phenotype is associated with complex genotypic changes in the protease. Resistance necessitates the sequential accumulation of multiple mutations. (c) 2005 Elsevier B.V. All rights reserved.