Prasad V R, Lowy I, de los Santos T, Chiang L, Goff S P
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11363-7. doi: 10.1073/pnas.88.24.11363.
The appearance of drug-resistant strains of viral pathogens is a major difficulty confounding current efforts to block viral infections. The identification and analysis of mutations responsible for drug resistance can provide important clues helpful in understanding the mechanisms of resistance and in the eventual development of better therapies. We have used a direct screening method to scan libraries of mutagenized genes encoding the reverse transcriptase of human immunodeficiency virus type 1, and have recovered a variant enzyme that is resistant to the chain-terminator inhibitor 2',3'-dideoxyguanosine triphosphate. The single substitution mutation in this variant conferred broad crossresistance to a variety of other antiviral compounds currently in clinical trials. Virus carrying the mutation was fully infectious in cultured human lymphocytes. The replication of the mutant virus was highly resistant to phosphonoformic acid but did not show increased resistance to the prodrug dideoxyguanosine.
病毒病原体耐药菌株的出现是当前阻碍病毒感染防治工作的一个主要难题。对耐药相关突变的鉴定和分析能够为理解耐药机制以及最终研发出更好的治疗方法提供重要线索。我们采用了一种直接筛选方法来扫描编码人类免疫缺陷病毒1型逆转录酶的诱变基因文库，并获得了一种对链终止抑制剂2',3'-双脱氧鸟苷三磷酸具有抗性的变异酶。该变异体中的单取代突变赋予了对目前正在临床试验中的多种其他抗病毒化合物的广泛交叉抗性。携带该突变的病毒在培养的人类淋巴细胞中具有完全传染性。突变病毒的复制对膦甲酸具有高度抗性，但对前体药物双脱氧鸟苷并未表现出抗性增加。
