Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens
Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens
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DOI：
10.1086/386291
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发表时间：
2004-05-15
影响因子：
6.4
通讯作者：
Friborg, J
中科院分区：
文献类型：
--
作者：
Colonno, R;Rose, R;Friborg, J
阿特拉那韦(ATV)是一种每天一次的人类免疫缺陷病毒(HIV)蛋白酶抑制剂(PI)，被证明是有效的，耐受性良好。与其他PI相比，ATV具有明显的耐药性，对1-2个PI耐药的分离物中86%保持敏感性。在接受含有ATV的方案时，从被指定为经历病毒学失败的PI-naive患者获得的临床分离株在HIV-1蛋白酶的氨基酸残基50(I50L)处含有独特的从异亮氨酸到亮氨酸的替代。在所有对ATV表现出表型抗性的分离株中观察到的I50L替换出现在各种不同的背景下，并经常伴随A71V、K45R和/或G73S。含有I50L替换的病毒生长受损，表现出对ATV的特异性抗性，并且对其他PI的敏感性增加(小于或等于参考毒株的0.4)。携带I50L的病毒与携带I50V的病毒比较，分别对ATV和Amprenavir具有特异性耐药，没有交叉耐药的证据。独特的I50L替换是对亚冠病毒耐药的标志性突变。
Atazanavir (ATV) is a once-daily human immunodeficiency virus (HIV) protease inhibitor (PI) shown to be effective and well tolerated. ATV has a distinct resistance profile relative to other PIs, with susceptibility maintained against 86% of isolates resistant to 1 - 2 PIs. Clinical isolates obtained from PI-naive patients designated as experiencing virologic failure while receiving ATV-containing regimens contained a unique isoleucine-to-leucine substitution at amino acid residue 50 (I50L) of the HIV-1 protease. The I50L substitution, observed in all isolates exhibiting phenotypic resistance to ATV, emerged in a variety of different backgrounds and was most frequently accompanied by A71V, K45R, and/or G73S. Viruses containing an I50L substitution were growth impaired, displayed ATV-specific resistance, and had increased susceptibilities ( less than or equal to0.4 of reference strain) to other PIs. Comparison of viruses bearing I50L with those bearing I50V revealed specific resistance to ATV and amprenavir, respectively, with no evidence of cross-resistance. The unique I50L substitution is the signature mutation for resistance to ATV.