Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors
Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors
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DOI：
10.1016/j.virol.2008.04.032
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发表时间：
2008-08-01
期刊：
影响因子：
3.7
通讯作者：
Moore, John P.
中科院分区：
文献类型：
--
作者：
Pugach, Pavel;Ketas, Thomas J.;Moore, John P.
小分子CCR 5抑制剂是一类新的治疗人类免疫缺陷病毒I型（HIV-1）感染的药物。它们通过与CCR 5辅助受体结合并阻止其在HIV-1细胞融合期间的使用而起作用。逃逸突变体可以在体外针对CCR 5抑制剂产生，并且将在这些药物临床使用时产生。在这里，我们评估了CCR 5耐药病毒对其他通过不同机制起作用的抗逆转录病毒药物的反应，以及它们对中和抗体（NAb）的敏感性。后一项研究的基本原理是，CCR 5抑制剂的耐药途径涉及HIV-1包膜糖蛋白（Env）的变化，这也是NAb的靶点。逃逸突变体CC101.19和D1/85.16分别从原代R5 HIV-1分离株CC 1/85中筛选出对AD 101和维克韦罗（VVC）的耐药性。每种逃逸突变体对其他小分子CCR 5抑制剂（aplaviroc、maraviroc、VVC、AD 101和CMPD 167）具有交叉耐药性，但对CCR 5的蛋白质配体敏感：修饰的趋化因子PSC-RANTES和人源化MAb PRO-140。耐药病毒还保留了野生型对核苷逆转录酶抑制剂（RTI）齐多夫定、非核苷RTI奈韦拉平、蛋白酶抑制剂阿扎那韦和其他独立于CCR 5发挥作用的附着和融合抑制剂（BMS-806、PRO-542和恩夫韦肽）的敏感性。值得注意的是，逃逸突变体比亲本CC 1/85分离株对中和单克隆抗体的子集和来自HIV-1感染者的一些血清更敏感，这意味着赋予对CCR 5抑制剂抗性的Env序列变化可以增加一些NAb表位的可及性。因此，保持NAb抗性的需要可能是对体内如何发生CCR 5抑制剂逃逸的限制。(C)2008年爱思唯尔公司All rights reserved.
The small molecule CCR5 inhibitors are a new class of drugs for treating infection by human immunodeficiency virus type I (HIV-1). They act by binding to the CCR5 co-receptor and preventing its use during HIV-1-cell fusion. Escape mutants can be raised against CCR5 inhibitors in vitro and will arise when these drugs are used clinically. Here, we have assessed the responses of CCR5 inhibitor-resistant viruses to other anti-retroviral drugs that act by different mechanisms, and their sensitivities to neutralizing antibodies (NAbs). The rationale for the latter study is that the resistance pathway for CCR5 inhibitors involves changes in the HIV-1 envelope glycoproteins (Env), which are also targets for NAbs. The escape mutants CC101.19 and D1/85.16 were selected for resistance to AD101 and vicriviroc (VVC), respectively, from the primary R5 HIV-1 isolate CC1/85. Each escape mutant was cross-resistant to other small molecule CCR5 inhibitors (aplaviroc, maraviroc, VVC, AD101 and CMPD 167), but sensitive to protein ligands of CCR5: the modified chemokine PSC-RANTES and the humanized MAb PRO-140. The resistant viruses also retained wild-type sensitivity to the nucleoside reverse transcriptase inhibitor (RTI) zidovudine, the non-nucleoside RTI nevirapine, the protease inhibitor atazanavir and other attachment and fusion inhibitors that act independently of CCR5 (BMS-806, PRO-542 and enfuvirtide). Of note is that the escape mutants were more sensitive than the parental CC1/85 isolate to a subset of neutralizing monoclonal antibodies and to some sera from HIV-1-infected people, implying that sequence changes in Env that confer resistance to CCR5 inhibitors can increase the accessibility of some NAb epitopes. The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo. (C) 2008 Elsevier Inc. All rights reserved.