Irlbeck David M, Amrine-Madsen Heather, Kitrinos Kathryn M, Labranche Celia C, Demarest James F
GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
AIDS. 2008 Jul 31;22(12):1425-31. doi: 10.1097/QAD.0b013e32830184ba.
HIV-1 utilizes CD4 and either chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4) to gain entry into host cells. Small molecule CCR5 antagonists are currently being developed for the treatment of HIV-1 infection. Because HIV-1 may also use CXCR4 for entry, the use of CCR5 entry inhibitors is controversial for patients harboring CCR5-using and CXCR4-using (dual/mixed-tropic) viruses. The goal of the present study was to determine the proportion of CCR5-tropic and CXCR4-tropic viruses in dual/mixed-tropic virus isolates from drug-naïve patients and the phenotypic and genotypic relationships of viruses that use CCR5 or CXCR4 or both.
Fourteen antiretroviral-naive HIV-1-infected patients were identified as having population coreceptor tropism readout of dual/mixed-tropic viruses. Intrapatient comparisons of coreceptor tropism and genotype of env clones were conducted on plasma virus from each patient.
Population HIV-1 envelope tropism and susceptibility to the CCR5 entry inhibitor, aplaviroc, were performed using the Monogram Biosciences Trofile Assay. Twelve env clones from each patient were analyzed for coreceptor tropism, aplaviroc sensitivity, genotype, and intrapatient phylogenetic relationships.
Viral populations from antiretroviral-naive patients with dual/mixed-tropic virus are composed primarily of CCR5-tropic env clones mixed with those that use both coreceptors (R5X4-tropic) and, occasionally, CXCR4-tropic env clones. Interestingly, the efficiency of CXCR4 use by R5X4-tropic env clones varied with their genetic relationships to CCR5-tropic env clones from the same patient.
These data show that the majority of viruses in these dual/mixed-tropic populations use CCR5 and suggest that antiretroviral-naive patients may benefit from combination therapy that includes CCR5 entry inhibitors.
HIV-1利用CD4以及趋化因子（C-C基序）受体5（CCR5）或趋化因子（C-X-C基序）受体4（CXCR4）进入宿主细胞。目前正在研发小分子CCR5拮抗剂用于治疗HIV-1感染。由于HIV-1也可能利用CXCR4进入细胞，对于携带利用CCR5和利用CXCR4（双嗜性/混合嗜性）病毒的患者，使用CCR5进入抑制剂存在争议。本研究的目的是确定初治患者双嗜性/混合嗜性病毒分离株中CCR5嗜性和CXCR4嗜性病毒的比例，以及利用CCR5或CXCR4或两者的病毒的表型和基因型关系。
14例未接受过抗逆转录病毒治疗的HIV-1感染患者被确定为具有双嗜性/混合嗜性病毒的群体共受体嗜性读数。对每位患者血浆病毒进行共受体嗜性和env克隆基因型的患者内比较。
使用Monogram Biosciences Trofile检测法检测群体HIV-1包膜嗜性以及对CCR5进入抑制剂阿普洛韦的敏感性。分析每位患者的12个env克隆的共受体嗜性、阿普洛韦敏感性、基因型以及患者内系统发育关系。
来自未接受过抗逆转录病毒治疗且具有双嗜性/混合嗜性病毒的患者的病毒群体主要由CCR5嗜性env克隆与同时利用两种共受体（R5X4嗜性）的env克隆混合组成，偶尔还有CXCR4嗜性env克隆。有趣的是，R5X4嗜性env克隆利用CXCR4的效率因其与同一患者CCR5嗜性env克隆的遗传关系而异。
这些数据表明，这些双嗜性/混合嗜性群体中的大多数病毒利用CCR5，并提示未接受过抗逆转录病毒治疗的患者可能从包括CCR5进入抑制剂的联合治疗中获益。
