V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc

被引:29
|
作者
Berro, Reem [1 ]
Klasse, Per Johan [1 ]
Moore, John P. [1 ]
Sanders, Rogier W. [1 ,2 ]
机构
[1] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA
[2] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands
基金
欧洲研究理事会;
关键词
CCR5; Small molecule CCR5 inhibitors; V3; sequence; Drug resistance; NT; Maraviroc; Vicriviroc; IMMUNODEFICIENCY-VIRUS TYPE-1; SMALL-MOLECULE INHIBITOR; CHEMOKINE RECEPTOR CCR5; N-TERMINUS; RESISTANCE; GP120; ANTAGONIST; POTENT; CORECEPTOR; MUTATIONS;
D O I
10.1016/j.virol.2012.02.006
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
HIV-1 develops resistance to CCR5 antagonists such as Maraviroc (MVC) and Vicriviroc (VVC) both in vitro and in vivo, with most changes arising in the gp120 V3 region. Both compounds bind to the same hydrophobic cavity in CCR5 in subtly different ways. Here, we investigated which V3 sequence changes are most associated with MVC and VVC resistance and how they affect the interaction between gp120 and the CCR5 NT. We found that WCand MVC-selected amino acid changes map to different V3 locations and involve residues that interact with the CCR5 NT in different ways. Changes in VVC-selected, but not MVC-selected, variants often involve charged residues. Although the overall V3 charge tends not to change, the introduction or removal of charged residues at specific positions affects the local electrostatic potential and could have structural and functional implications. In summary, VVC and MVC trigger the evolution of distinct HIV-1 resistance patterns in V3. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:158 / 165
页数:8
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