AZT-resistant foamy virus
AZT-resistant foamy virus
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DOI：
10.1016/j.virol.2007.08.025
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发表时间：
2008-01-05
期刊：
影响因子：
3.7
通讯作者：
Rethwilm, Axel
中科院分区：
文献类型：
--
作者：
Kretzschmar, Benedikt;Nowrouzi, Ali;Rethwilm, Axel
叠氮胸苷（AZT）是一种逆转录酶（RT）抑制剂，可有效阻断逆转录病毒或泡沫病毒（FV）的复制。为了更精确地阐明FV RT酶的作用机制，我们在细胞培养物中产生了AZT抗性FV。从猕猴（SFVmac），这是不敏感的AZT浓度为1毫米，但不是来自黑猩猩的FV猴泡沫病毒获得生物抗性病毒。核苷酸测序显示pol基因中有四个非沉默突变。将这些突变引入感染性分子克隆鉴定了SFVmac的完全AZT抗性表型所需的所有变化。单个位点的改变表明，SFVmac中的AZT耐药性可能是通过以确定的顺序连续获得pol突变而获得的，因为无论是否存在AZT，一些改变本身都不会导致有效复制的病毒。将突变引入密切相关的原型FV（PFV）的RT中并没有产生AZT抗性病毒，相反，它们显著损害了病毒适应性。(c)2007爱思唯尔公司All rights reserved.
Azidothymidine (AZT) is a reverse transcriptase (RT) inhibitor that efficiently blocks the replication of spumaretroviruses or foamy viruses (FVs). To more precisely elucidate the mechanism of action of the FV RT enzyme, we generated an AZT-resistant FV in cell culture. Biologically resistant virus was obtained for simian foamy virus from macaque (SFVmac), which was insensitive to AZT concentrations of 1 mM, but not for FVs derived from chimpanzees. Nucleotide sequencing revealed four non-silent mutations in the pol gene. Introduction of these mutations into an infectious molecular clone identified all changes to be required for the fully AZT-resistant phenotype of SFVmac. The alteration of individual sites showed that AZT resistance in SFVmac was likely acquired by consecutive acquisition of pol mutations in a defined order, because some alterations on their own did not result in an efficiently replicating virus, neither in the presence nor in the absence of AZT. The introduction of the mutations into the RT of the closely related prototypic FV (PFV) did not yield an AZT-resistant virus, instead they significantly impaired the viral fitness. (c) 2007 Elsevier Inc. All rights reserved.