Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists
Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists
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DOI：
10.1099/jgv.0.000536
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发表时间：
2016-09-01
影响因子：
3.8
通讯作者：
Murakami, Tsutomu
中科院分区：
文献类型：
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作者：
Hikichi, Yuta;Yokoyama, Masaru;Murakami, Tsutomu
在存在趋化因子受体拮抗剂的情况下，HIV-1在细胞培养物中的传代可导致选择具有赋予对这些抑制剂的抗性的env突变的病毒。在本研究中，我们研究了HIV-1 env突变对中和抗体（NAb）的敏感性的影响，这些突变赋予了对CXCR 4拮抗剂的抗性。在CXCR 4拮抗剂KRH-3955、AMD 3100和AMD 070的作用下，嗜CXCR 4的HIV-1 NL 4 -3在PM 1/CCR 5细胞中连续传代，产生了两种KRH-3955耐药病毒、一种AMD 3100耐药病毒和一种AMD 070耐药病毒。这些病毒具有多个env突变，包括Env gp 120 V3区。与NL 4 -3 WT病毒相比，具有这些CXCR 4拮抗剂抗性Env的大多数病毒对分别靶向V3区、gp 120 CD 4结合位点和gp 41膜近端区的NAb 447- 52 D、b12和2F 5显示出更高的敏感性。V3编码区被CXCR 4拮抗剂抗性病毒的V3编码区替换的重组NL 4 -3病毒显示出对NAb b12、2F 5和447- 52 D的敏感性增加。Env gp 120外部结构域的分子动力学模拟预测，V3突变增加了V3环的顶端和茎部的波动水平。这些结果表明，在V3编码区的突变，导致病毒的CXCR 4拮抗剂的敏感性的损失增加病毒的敏感性NAB，提供了深入了解我们的病毒Env的可及性趋化因子受体和敏感性NAB的相互作用。
HIV-1 passage in cell culture in the presence of chemokine receptor antagonists can result in selection of viruses with env mutations that confer resistance to these inhibitors. In the present study, we examined the effect of HIV-1 env mutations that confer resistance to CXCR4 antagonists on envelope (Env) sensitivity to neutralizing antibodies (NAbs). Serial passage of CXCR4-tropic HIV-1 NL4-3 in PM1/CCR5 cells under CXCR4 antagonists KRH-3955, AMD3100 and AMD070 yielded two KRH-3955-resistant, one AMD3100-resistant and one AMD070-resistant viruses. These viruses had multiple env mutations including the Env gp120 V3 region. The majority of viruses having these CXCR4 antagonist-resistant Envs showed higher sensitivity to NAbs 447-52D, b12 and 2F5 targeting the V3 region, the gp120 CD4-binding site and the gp41 membrane proximal region, respectively, compared to NL4-3 WT virus. Recombinant NL4-3 viruses with the V3-coding region replaced with those derived from the CXCR4 antagonist-resistant viruses showed increased sensitivity to NAbs b12, 2F5 and 447-52D. Molecular dynamics simulations of Env gp120 outer domains predicted that the V3 mutations increased levels of fluctuations at the tip and stem of the V3 loop. These results indicate that mutations in the V3-coding region that result in loss of viral sensitivity to CXCR4 antagonists increase viral sensitivity to NAbs, providing insights into our understanding of the interplay of viral Env accessibility to chemokine receptors and sensitivity to NAbs.