Identification of two distinct human immunodeficiency virus type 1 Vif determinants critical for interactions with human APOBEC3G and APOBEC3F

被引:196
作者
Russell, Rebecca A. [1 ]
Pathak, Vinay K. [1 ]
机构
[1] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Canc Res Ctr,NIH, Frederick, MD 21702 USA
关键词
D O I
10.1128/JVI.00395-07
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) inhibit replication of Vif-deficient human immunodeficiency virus type I (HIV-1). HIV-1 Vif overcomes these host restriction factors by binding to them and inducing their proteasomal degradation. The Vif-A3G and Vif-A3F interactions are attractive targets for antiviral drug development because inhibiting the interactions could allow the host defense mechanism to control HIV-1 replication. It was recently reported that the Vif amino acids (DRMR17)-R-14 are important for functional interaction and degradation of the previously identified Vif-resistant mutant of A3G (D128K-A3G). However, the Vif determinants important for functional interaction with A3G and A3F have not been fully characterized. To identify these determinants, we performed an extensive mutational analysis of HIV-1 Vif. Our analysis revealed two distinct Vif determinants, amino acids (YRHHY44)-R-40 and (DRMR17)-R-14, which are essential for binding to A3G and A3F, respectively. Interestingly, mutation of the A3G-binding region increased Vif's ability to suppress A3F. Vif binding to D128K-A3G was also dependent on the (YRHHY44)-R-40 region but not the (DRMR17)-R-14 region. Consistent with previous observations, subsequent neutralization of the D128K-A3G antiviral activity required substitution of Vif determinant (DRMR17)-R-14 with SEMQ, similar to the SERQ amino acids in simian immunodeficiency virus SIVAGM Vif, which is capable of neutralizing D128K-A3G. These studies are the first to clearly identify two distinct regions of Vif that are critical for independent interactions with A3G and A3F. Pharmacological interference with the Vif-A3G or Vif-A3F interactions could result in potent inhibition of HIV-1 replication by the APOBEC3 proteins.
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页码:8201 / 8210
页数:10
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