Merck Research Laboratories, Department of Infectious Diseases, 2015 Galloping Hill Road, K-15-4945, Kenilworth, NJ 07033, USA.
Virology. 2010 Apr 25;400(1):145-55. doi: 10.1016/j.virol.2010.01.037. Epub 2010 Feb 21.
The HIV-1 CCR5 co-receptor is a member of the chemokine receptor family of G-protein coupled receptors; for which a number of small molecule antagonists, such as vicriviroc (VCV), have been developed to inhibit HIV-1 R5-tropic replication. In this study, we analyzed an HIV-1 subtype D envelope gene from a clinical trial subject who developed complete resistance to VCV. The HIV-1 resistant envelope has six predominant amino acid changes in the V3 loop, together with one change in the C4 domain of gp120, which are fully responsible for the resistance phenotype. V3 loop mutations Q315E and R321G are essential for resistance to VCV, whereas E328K and G429R in C4 contribute significantly to the infectivity of the resistant variant. Collectively, these amino acid changes influenced the interaction of gp120 with both the N-terminus and ECL2 region of CCR5.
HIV-1 CCR5 共受体是 G 蛋白偶联受体趋化因子受体家族的成员；已经开发出许多小分子拮抗剂，如维立西罗（VCV），以抑制 HIV-1 R5 嗜性复制。在这项研究中，我们分析了一位临床试验受试者的 HIV-1 亚型 D 包膜基因，该受试者对 VCV 产生了完全耐药。HIV-1 耐药包膜在 V3 环中具有六个主要的氨基酸变化，同时在 gp120 的 C4 结构域中发生一个变化，这完全是耐药表型的原因。V3 环突变 Q315E 和 R321G 对于 VCV 的耐药性是必需的，而 C4 中的 E328K 和 G429R 对耐药变体的感染性有重要贡献。总的来说，这些氨基酸变化影响了 gp120 与 CCR5 的 N 端和 ECL2 区域的相互作用。
