MULTIPLE MUTATIONS IN HIV-1 REVERSE-TRANSCRIPTASE CONFER HIGH-LEVEL RESISTANCE TO ZIDOVUDINE (AZT)
MULTIPLE MUTATIONS IN HIV-1 REVERSE-TRANSCRIPTASE CONFER HIGH-LEVEL RESISTANCE TO ZIDOVUDINE (AZT)
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DOI：
10.1126/science.2479983
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发表时间：
1989-12-01
期刊：
影响因子：
56.9
通讯作者：
KEMP, SD
中科院分区：
文献类型：
--
作者：
LARDER, BA;KEMP, SD
与获得性免疫缺陷综合征（AIDS）或与AIDS相关的复合物的个体，人类免疫缺陷病毒（HIV）分离株具有降低对Zidovudine（3'' - Azido-3'' - 脱氧胸苷，AZT）的敏感性的人的敏感性（HIV）。反抗。大多数是在治疗开始和期间获得的顺序分离株。来自五对敏感和抗性分离株的逆转录酶（RT）编码区的比较核苷酸序列分析确定了所有抗性菌株共有的三种预测的氨基酸取代（ASP67.fwdarw。Asn，lys70 .fwdarw。 phe或tyr）加上三个分离株中的第四个（lys219 .fwdarw。部分抗性分离株具有这四个变化的组合。 T细胞转染后，用这四个突变构建的传染性分子克隆产生了高度抗性的HIV。这些突变的可再现性质应该使得可以开发快速测定，以预测齐多夫丁通过表演聚合酶链链反应从外周血淋巴细胞中核酸扩增，从而绕开当前的HIV HIV分离和敏感性测试。
Human immunodeficiency virus (HIV) isolates with reduced sensitivity to zidovudine (3''-azido-3''-deoxythymidine, AZT) from individual with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were studied to determine the genetic basis of their resistance. Most were sequential isolates obtained at the initiation of and during therapy. Comparative nucleotide sequence analysis of the reverse transcriptase (RT) coding region from five pairs of sensitive and resistant isolates identified three predicted amino acid substitutions common to all the resistant strains (Asp67 .fwdarw. Asn, Lys70 .fwdarw. Arg, Thr215 .fwdarw. Phe or Tyr) plus a fourth in three isolates (Lys219 .fwdarw. Gln). Partially resistant isolates had combinations of these four changes. An infectious molecular clone constructed with these four mutations in RT yielded highly resistant HIV after transfection of T cells. The reproducible nature of these mutations should make it possible to develop rapid assays to predict zidovudine resistance by performig polymerase chain reaction amplification of nucleic acid from peripheral blood lymphocytes, thereby circumventing current HIV isolation and sensitivity testing.