Generation of human TRIM5α mutants with high HIV-1 restriction activity

被引:0
|
作者
Q T Pham
A Bouchard
M G Grütter
L Berthoux
机构
[1] Laboratory of Retrovirology,Department of Biochemistry
[2] University of Québec,undefined
[3] Biochemisches Institut,undefined
[4] University of Zurich,undefined
来源
Gene Therapy | 2010年 / 17卷
关键词
HIV-1; lentivirus; random mutagenesis; TRIM5α; restriction factor; retroviral replication;
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学科分类号
摘要
Rhesus macaque tripartite motif (TRIM)5α potently inhibits early stages of human immunodeficiency virus (HIV)-1 replication, while the human orthologue has little effect on this virus. We used PCR-based random mutagenesis to construct a large library of human TRIM5α variants containing mutations in the PRYSPRY domain. We then applied a functional screen to isolate human cells made resistant to HIV-1 infection by the expression of a mutated TRIM5α. This protocol led to the characterization of a human TRIM5α variant containing a mutation at arginine 335 as conferring resistance to HIV-1 infection. The level of protection stemming from expression of this mutant was comparable to that of previously described mutations at position 332. R332/R335 double mutants decreased permissiveness to HIV-1 and to other lentiviruses by 20- to 50-fold in TE671 fibroblasts and in the T-cell line SUP-T1, and prevented HIV-1 spreading infection as efficiently as the rhesus macaque TRIM5α orthologue did. The finding that only two substitutions in human TRIM5α can confer resistance to HIV-1 at levels as high as one of the most potent natural orthologues of TRIM5α removes a roadblock toward the use of this restriction factor in human gene therapy applications.
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页码:859 / 871
页数:12
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