D'huys Thomas, Claes Sandra, Van Loy Tom, Schols Dominique
Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
Heliyon. 2018 Mar 1;4(3):e00557. doi: 10.1016/j.heliyon.2018.e00557. eCollection 2018 Mar.
Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and HIV-2 entry . In this study, a cellular infection model was established to further decipher the role of CXCR7 as an HIV coreceptor. Using this model, CXCR7-mediated viral entry was demonstrated for several clinical HIV isolates as well as laboratory strains. Of interest, the X4-tropic HIV-1 HE strain showed rapid adaptation towards CXCR7-mediated infection after continuous passaging on CD4- and CXCR7-expressing cells. Furthermore, we uncovered anti-CXCR7 monoclonal antibodies, small molecule CXCR7 inhibitors and the natural CXCR7 chemokine ligands as potent inhibitors of CXCR7 receptor-mediated HIV entry and replication. Even though the clinical relevance of CXCR7-mediated HIV infection remains poorly understood, our data suggest that divergent HIV-1 and HIV-2 strains can quickly adapt their coreceptor usage depending on the cellular environment, which warrants further investigation.
趋化因子受体CCR5和CXCR4被认为是HIV初始感染、复制和传播以及后续艾滋病进展的主要共受体。多年来，属于G蛋白偶联受体家族的其他趋化因子受体也已被鉴定为HIV进入人类宿主细胞的候选共受体。其中，CXCR7，也被称为非典型趋化因子受体3（ACKR3），被认为是一种能够促进HIV-1和HIV-2进入的共受体候选物。在本研究中，建立了一种细胞感染模型以进一步解读CXCR7作为HIV共受体的作用。使用该模型，证实了几种临床HIV分离株以及实验室菌株可通过CXCR7介导病毒进入。有趣的是，X4嗜性HIV-1 HE株在表达CD4和CXCR7的细胞上连续传代后，显示出对CXCR7介导感染的快速适应性。此外，我们发现抗CXCR7单克隆抗体、小分子CXCR7抑制剂以及天然CXCR7趋化因子配体是CXCR7受体介导的HIV进入和复制的有效抑制剂。尽管CXCR7介导的HIV感染的临床相关性仍知之甚少，但我们的数据表明，不同的HIV-1和HIV-2毒株可根据细胞环境快速调整其共受体使用情况，这值得进一步研究。
