Department of Virology, Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
J Antimicrob Chemother. 2011 Apr;66(4):890-5. doi: 10.1093/jac/dkq535. Epub 2011 Jan 28.
Maraviroc is the first licensed chemokine co-receptor 5 (CCR5) co-receptor antagonist in clinical practice. It is currently being used in patients harbouring exclusively CCR5-tropic virus. The objective of the study was to investigate the impact of maraviroc on viruses with different co-receptor preferences in a patient with a dual/mixed (D/M) infection.
We present a case report of an HIV-1 patient infected with a D/M virus population. Co-receptor tropism was determined by phenotypic and genotypic tests. Biological clones from pre- and post-maraviroc therapy were generated. Tropism of these infectious clones was investigated in U373-MAGI cells expressing CD4+ CCR5+ or CD4+ CXCR4+. Maraviroc susceptibility and viral replication were determined using donor peripheral blood mononuclear cells (PBMCs).
In-depth clonal genotypic analysis revealed the presence of both R5-tropic variants and X4-tropic viruses before the start of maraviroc. During maraviroc therapy all R5-predicted viruses were suppressed. Phenotypic analyses revealed that all biological clones before maraviroc therapy could infect both CCR5- and CXCR4-bearing U373-MAGI cells, demonstrating dual tropism. The baseline biological clones preferentially infected the CCR5 cell line and were fully susceptible to maraviroc in PBMCs (dual-R5). In contrast, during maraviroc therapy the dual-R5-tropic viruses were replaced by more X4-tropic viruses (dual-X4), which could not be inhibited by maraviroc.
This case report demonstrates that dual-tropic viruses, capable of using both co-receptors in phenotypic assays, can be inhibited by maraviroc if they have a CCR5 co-receptor preference in vivo.
马拉维若（maraviroc）是首个在临床实践中应用的化学趋化因子受体 5（CCR5）共受体拮抗剂。目前，马拉维若仅用于仅携带 CCR5 嗜性病毒的患者。本研究的目的是在携带双重/混合（D/M）感染的患者中，研究马拉维若对不同共受体嗜性病毒的影响。
我们报告了一例 HIV-1 患者感染双重/混合病毒的病例。通过表型和基因型检测确定共受体嗜性。从治疗前和治疗后生成生物克隆。将这些感染性克隆在表达 CD4+CCR5+或 CD4+CXCR4+的 U373-MAGI 细胞中研究其嗜性。使用供体外周血单核细胞（PBMC）测定马拉维若的敏感性和病毒复制。
深入的克隆基因型分析显示，在开始使用马拉维若之前，存在 R5 嗜性变异体和 X4 嗜性病毒。在马拉维若治疗期间，所有 R5 预测的病毒均被抑制。表型分析显示，在马拉维若治疗前的所有生物学克隆均可以感染携带 CCR5 和 CXCR4 的 U373-MAGI 细胞，表现出双重嗜性。基线生物学克隆优先感染 CCR5 细胞系，在 PBMC 中对马拉维若完全敏感（双重 R5）。相比之下，在马拉维若治疗期间，双重 R5 嗜性病毒被更多的 X4 嗜性病毒取代（双重 X4），马拉维若无法抑制其复制。
本病例报告表明，在表型检测中能够使用两种共受体的双重嗜性病毒，如果其在体内对 CCR5 共受体具有偏好性，则可以被马拉维若抑制。
