Viral evolution in response to the broad-based retroviral protease inhibitor TL-3

被引:22
作者
Bühler, B
Lin, YC
Morris, G
Olson, AJ
Wong, CH
Richman, DD
Elder, JH
Torbett, BE
机构
[1] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[3] San Diego VA Healthcare Syst, La Jolla, CA 92161 USA
[4] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[6] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
关键词
D O I
10.1128/JVI.75.19.9502-9508.2001
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
TL-3 is a protease inhibitor developed using the feline immunodeficiency virus protease as a model. It has been shown to efficiently inhibit replication of human, simian, and feline immunodeficiency viruses and therefore has broad-based activity. We now demonstrate that TL-3 efficiently inhibits the replication of 6 of 12 isolates with confirmed resistance mutations to known protease inhibitors. To dissect the spectrum of molecular changes in protease and viral properties associated with resistance to TL-3, a panel of chronological in vitro escape variants was generated. We have virologically and biochemically characterized mutants with one (V82A), three (M461/F53L/V82A), or six (L24I/M46I/F53L/L63P/V77I/V82A) changes in the protease and structurally modeled the protease mutant containing six changes. Virus containing six changes was found to be 17-fold more resistant to TL-3 in cell culture than was wild-type virus but maintained similar in vitro replication kinetics compared to the wild-type virus. Analyses of enzyme activity of protease variants with one, three, and six changes indicated that these enzymes, compared to mild-type protease, retained 40, 47, and 61% activity, respectively. These results suggest that deficient protease enzymatic activity is sufficient for function, and the observed protease restoration might imply a selective advantage, at least in vitro, for increased protease activity.
引用
收藏
页码:9502 / 9508
页数:7
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