对2'，3'-双脱氧胞苷具有抗性的猫免疫缺陷病毒突变体的筛选与鉴定
Selection and characterization of a mutant of feline immunodeficiency virus resistant to 2',3'-dideoxycytidine.
作者信息
Medlin H K, Zhu Y Q, Remington K M, Phillips T R, North T W
机构信息
Division of Biological Sciences, University of Montana, Missoula 59812, USA.
出版信息
Antimicrob Agents Chemother. 1996 Apr;40(4):953-7. doi: 10.1128/AAC.40.4.953.
Abstract
We have selected and plaque purified a mutant of feline immunodeficiency virus (FIV) that is resistant to 2',3'-dideoxycytidine (ddC). This mutant was selected in cultured cells in the continuous presence of 25 microM ddC. The mutant, designated DCR-5c, was fourfold resistant to ddC, threefold resistant to 2',3'-dideoxyinosine, and more than fourfold resistant to phosphonoformic acid. DCR-5c displayed little or no resistance to (-)-beta-2',3'-dideoxy-3'-thiacytidine, 3'-azido-3'-deoxythymidine, or 9-(2-phosphonylmethoxyethyl) adenine. Reverse transcriptase purified from DCR-5c was less susceptible to inhibition by ddCTP, phosphonoformic acid, ddATP, or azido-dTTP than the wild-type FIV reverse transcriptase. Sequence analysis of DCR-5c revealed a single base change (G to C at nucleotide 2342) in the reverse transcriptase-encoding region of FIV. This mutation results in substitution of His for Asp at codon 3 of FIV reverse transcriptase. The role of this mutation in ddC resistance was confirmed by site-directed mutagenesis.
摘要
我们筛选并通过噬菌斑纯化了一株对2',3'-二脱氧胞苷（ddC）具有抗性的猫免疫缺陷病毒（FIV）突变体。该突变体是在含有25微摩尔ddC的培养细胞中持续筛选得到的。这个名为DCR-5c的突变体对ddC具有四倍抗性，对2',3'-二脱氧肌苷具有三倍抗性，对膦甲酸具有四倍以上抗性。DCR-5c对（-）-β-2',3'-二脱氧-3'-硫代胞苷、3'-叠氮-3'-脱氧胸苷或9-（2-膦酰甲氧基乙基）腺嘌呤几乎没有抗性。从DCR-5c中纯化得到的逆转录酶比野生型FIV逆转录酶更不易受到ddCTP、膦甲酸、ddATP或叠氮-dTTP的抑制。对DCR-5c的序列分析显示，FIV逆转录酶编码区有一个单碱基变化（核苷酸2342处的G变为C）。这种突变导致FIV逆转录酶第3密码子处的天冬氨酸被组氨酸取代。通过定点诱变证实了这种突变在ddC抗性中的作用。
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