Altered sensitivity of an R5X4 HIV-1 strain 89.6 to coreceptor inhibitors by a single amino acid substitution in the V3 region of gp120
Altered sensitivity of an R5X4 HIV-1 strain 89.6 to coreceptor inhibitors by a single amino acid substitution in the V3 region of gp120
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DOI：
10.1016/j.antiviral.2007.11.001
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发表时间：
2008-02-01
影响因子：
7.6
通讯作者：
Harada, Shinji
中科院分区：
文献类型：
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作者：
Maeda, Yosuke;Yusa, Keisuke;Harada, Shinji
尽管靶细胞在体外同时表达 CXCR4 和 CCR5，但多种 R5X4 菌株的复制被 AMD3100 或 T140 等单一 CXCR4 抑制剂阻断。为了确定 Env 的哪些区域与 CXCR4 抑制剂敏感性增加有关，我们使用 R5X4 HIV-1 毒株 89.6 分离了 T140 逃逸突变体。一个分离的突变体在 Env 的 V3 区有一个氨基酸取代（精氨酸 308 变为丝氨酸 R308S）。用突变体 Env 假型化的荧光素酶报告基因 HIV-1 表明，这种取代赋予了对 CXCR4 拮抗剂的完全抗性，但在表达 CCR5 和 CXCR4 的细胞感染中增加了对 CCR5 拮抗剂 TAK-779 的敏感性。使用表达单个辅助受体的细胞进行的分析表明，突变体 Env 主要且有效地利用 CCR5 而不是 CXCR4，同时保留 R5X4 表型。这些结果表明，R5X4 菌株对辅助受体抑制剂的敏感性因 gp120 V3 区中的单个氨基酸取代而改变。 (C) 2007 Elsevier B.V. 保留所有权利。
The replication of several R5X4 strains is blocked by single CXCR4 inhibitors such as AMD3100 or T140 although the target cells express both CXCR4 and CCR5 in vitro. To identify which region(s) of the Env are involved in the increased sensitivity to CXCR4 inhibitors, we isolated a T140-escape mutant using R5X4 HIV-1 strain 89.6. An isolated mutant harbored a single amino acid substitution in the V3 region of the Env (arginine 308 to serine R308S). Luciferase-reporter HIV-1 pseudotyped with the mutant Env showed that the substitution conferred total resistance to CXCR4 antagonists but increased sensitivity to a CCR5 antagonist TAK-779 in the infection of the cells expressing both CCR5 and CXCR4. Analyses using the cells expressing a single coreceptor showed that the mutant Env predominantly and efficiently utilized CCR5 rather than CXCR4 while retaining R5X4 phenotype. These results indicated that the sensitivities of the R5X4 strain to coreceptor inhibitors were altered by a single amino acid substitution in the V3 region of gp120. (C) 2007 Elsevier B.V. All rights reserved.