A Maraviroc-Resistant HIV-1 with Narrow Cross-Resistance to Other CCR5 Antagonists Depends on both N-Terminal and Extracellular Loop Domains of Drug-Bound CCR5
A Maraviroc-Resistant HIV-1 with Narrow Cross-Resistance to Other CCR5 Antagonists Depends on both N-Terminal and Extracellular Loop Domains of Drug-Bound CCR5
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DOI：
10.1128/jvi.01109-10
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发表时间：
2010-10-01
影响因子：
5.4
通讯作者：
Doms, Robert W.
中科院分区：
文献类型：
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作者：
Tilton, John C.;Wilen, Craig B.;Doms, Robert W.
CCR5拮抗剂通过与辅助受体结合并诱导CCR5的细胞外环（ECL）的变化来抑制HIV进入。在这项研究中，我们分析了来自11名接受过治疗的患者的病毒，这些患者在接受含有CCR5拮抗剂马拉韦罗（MVC）的治疗方案时出现病毒学失败。在治疗过程中，一名患者的病毒对MVC产生了高水平的耐药性。尽管对一种CCR5拮抗剂的耐药性通常与对其他药物的广泛交叉耐药性相关，但这些病毒对大多数其他CCR5拮抗剂（包括vicriviroc和aplaviroc）仍然敏感。MVC抗性依赖于病毒包膜（Env）蛋白V3环内的突变，并受V4环中其他突变的调节。治疗前血浆病毒RNA的深度测序表明，尽管存在预测CXCR4使用的病毒序列，但药物结合的CCR5使用的演变似乎已经发生耐药性。在MVC治疗之前和期间从该患者获得的Env能够感染表达非常低的CCR5水平的细胞，表明辅助受体的高效使用。与先前报道的CCR5拮抗剂抗性病毒主要与CCR5的N末端相互作用相反，这些MVC抗性Env也依赖于CCR5的药物修饰的ECL进入。我们的研究结果表明，CCR5交叉耐药的模型，其中主要利用N末端的病毒广泛交叉耐多个CCR5拮抗剂，而需要的N末端和拮抗剂特异性ECL变化的病毒表现出狭窄的交叉耐药概况。
CCR5 antagonists inhibit HIV entry by binding to a coreceptor and inducing changes in the extracellular loops (ECLs) of CCR5. In this study, we analyzed viruses from 11 treatment-experienced patients who experienced virologic failure on treatment regimens containing the CCR5 antagonist maraviroc (MVC). Viruses from one patient developed high-level resistance to MVC during the course of treatment. Although resistance to one CCR5 antagonist is often associated with broad cross-resistance to other agents, these viruses remained sensitive to most other CCR5 antagonists, including vicriviroc and aplaviroc. MVC resistance was dependent upon mutations within the V3 loop of the viral envelope (Env) protein and was modulated by additional mutations in the V4 loop. Deep sequencing of pretreatment plasma viral RNA indicated that resistance appears to have occurred by evolution of drug-bound CCR5 use, despite the presence of viral sequences predictive of CXCR4 use. Envs obtained from this patient before and during MVC treatment were able to infect cells expressing very low CCR5 levels, indicating highly efficient use of a coreceptor. In contrast to previous reports in which CCR5 antagonist-resistant viruses interact predominantly with the N terminus of CCR5, these MVC-resistant Envs were also dependent upon the drug-modified ECLs of CCR5 for entry. Our results suggest a model of CCR5 cross-resistance whereby viruses that predominantly utilize the N terminus are broadly cross-resistant to multiple CCR5 antagonists, whereas viruses that require both the N terminus and antagonist-specific ECL changes demonstrate a narrow cross-resistance profile.