HIV-1 predisposed to acquiring resistance to maraviroc (MVC) and other CCR5 antagonists in vitro has an inherent, low-level ability to utilize MVC-bound CCR5 for entry

被引:35
作者
Roche, Michael [1 ,2 ]
Jakobsen, Martin R. [1 ,3 ]
Ellett, Anne [1 ]
Salimiseyedabad, Hamid [1 ]
Jubb, Becky [4 ]
Westby, Mike [4 ]
Lee, Benhur [5 ]
Lewin, Sharon R. [1 ,2 ,6 ]
Churchill, Melissa J. [1 ,7 ]
Gorry, Paul R. [1 ,2 ,8 ]
机构
[1] Burnet Inst, Ctr Virol, Melbourne, Vic, Australia
[2] Monash Univ, Dept Med, Melbourne, Vic 3004, Australia
[3] Aarhus Univ, Dept Med Microbiol & Immunol, DK-8000 Aarhus C, Denmark
[4] Pfizer Global Res & Dev, Sandwich, Kent, England
[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA
[6] Alfred Hosp, Infect Dis Unit, Melbourne, Vic, Australia
[7] Monash Univ, Dept Microbiol, Melbourne, Vic 3004, Australia
[8] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia
来源
RETROVIROLOGY | 2011年 / 8卷
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
SMALL-MOLECULE; INHIBITOR; TYPE-1; VICRIVIROC; ESCAPE; CELLS;
D O I
10.1186/1742-4690-8-89
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Background: Maraviroc (MVC) and other CCR5 antagonists are HIV-1 entry inhibitors that bind to- and alter the conformation of CCR5, such that CCR5 is no longer recognized by the viral gp120 envelope (Env) glycoproteins. Resistance to CCR5 antagonists results from HIV-1 Env acquiring the ability to utilize the drug-bound conformation of CCR5. Selecting for HIV-1 resistance to CCR5-antagonists in vitro is relatively difficult. However, the CCR5-using CC1/85 strain appears to be uniquely predisposed to acquiring resistance to several CCR5 antagonists in vitro including MVC, vicriviroc and AD101. Findings: Here, we show that Env derived from the parental CC1/85 strain is inherently capable of a low affinity interaction with MVC-bound CCR5. However, this phenotype was only revealed in 293-Affinofile cells and NP2-CD4/CCR5 cells that express very high levels of CCR5, and was masked in TZM-bl, JC53 and U87-CD4/CCR5 cells as well as PBMC, which express comparatively lower levels of CCR5 and which are more commonly used to detect resistance to CCR5 antagonists. Conclusions: Env derived from the CC1/85 strain of HIV-1 is inherently capable of a low-affinity interaction with MVC-bound CCR5, which helps explain the relative ease in which CC1/85 can acquire resistance to CCR5 antagonists in vitro. The detection of similar phenotypes in patients may identify those who could be at higher risk of virological failure on MVC.
引用
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页数:7
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