期刊
VIROLOGY
卷 306, 期 1, 页码 147-161出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0042-6822(02)00042-9
关键词
real-time polymerase chain reaction; integration; experimental antiviral agents; acquired immune deficiency syndrome; kinetics; biochemistry; drug resistance; HIV replication
类别
资金
- NIAID NIH HHS [5T32-AI07319, 5R01-AI41360] Funding Source: Medline
- NIGMS NIH HHS [5T32-GM07311, 5T32-GM08620] Funding Source: Medline
L-chicoric acid (L-CA) is a potent inhibitor of HIV integrase (IN) in vitro. In this report, the effects of a glycine to serine mutation at position 140 (G140S) on HIV IN and its effects on IN inhibitor resistance are described. HIV containing the G140S mutation showed a delay in replication. Using real-time polymerase chain reaction, the delay was secondary to a failure in integration. The mutant protein (ING140S) was attenuated approximately four-fold for catalysis under equilibrium conditions compared to wild-type IN (INWT) and attenuated five-fold in steady-state kinetic analysis of disintegration. Fifty percent inhibitory concentration assays were performed with IN inhibitors against both IN proteins in disintegration and strand transfer reactions. ING140S was resistant to both L-CA and L-731,988, a diketoacid. HIV containing the mutation was resistant to both inhibitors as well. The G140S mutation attenuates IN activity and confers resistance to IN inhibitors, suggesting that diketoacids and L-CA interact with a similar binding site on HIV IN. (C) 2003 Elsevier Science (USA). All rights reserved.
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