Laboratory of Retrovirology, CRP-Santé, Luxembourg, Luxembourg.
Antiviral Res. 2011 Dec;92(3):488-92. doi: 10.1016/j.antiviral.2011.10.003. Epub 2011 Oct 13.
Entry of Human Immunodeficiency Virus type 1 (HIV-1) into target cells is mediated by the CD4 receptor and a coreceptor, CCR5 or CXCR4. Maraviroc interferes with HIV entry by binding the CCR5 coreceptor. Virological failure to maraviroc-containing regimens can occur through the emergence of resistance, or through tropism evolution and broadened coreceptor usage. In the latter case, the physiological relevance of minority strains is a major concern. Here we report a retrospective analysis of coreceptor-usage and evolution based on 454-ultra-deep-sequencing of plasma and Peripheral Blood Mononuclear Cell (PBMC)-derived envelope V3-loops, accounting for coreceptor usage, from a patient who failed a maraviroc-containing regimen through the emergence of X4 strains. The X4 maraviroc-escape variant resulted from recombination between a long time archived proviral sequence from 2003 (5'-portion, including the V3-loop) and the dominant R5 strains circulating in plasma at the time of maraviroc-treatment initiation (3'-portion). Phylogenetic analyses and BEAST modeling highlighted that an early diverse viral quasispecies underwent a severe bottleneck following reinitiation of HAART and repeated IL-2 cycles between 1999 and 2001, leading to the transient outgrowth and archiving of one highly homogeneous X4 population from plasma, and to the expansion in plasma of one PBMC-derived R5 strain. Under maraviroc selective pressure, the early, no longer detectable X4 strains archived in PBMC were partially rescued to provide X4-determinants to the main circulating strain.
人类免疫缺陷病毒 1 型（HIV-1）进入靶细胞是由 CD4 受体和辅助受体 CCR5 或 CXCR4 介导的。马拉维若通过结合 CCR5 辅助受体来干扰 HIV 的进入。马拉维若包含的方案的病毒学失败可能是由于耐药性的出现，也可能是由于嗜性进化和广泛的辅助受体使用。在后一种情况下，少数株系的生理相关性是一个主要关注点。在这里，我们报告了一项基于对血浆和外周血单核细胞（PBMC）衍生包膜 V3 环的 454-超深度测序的核心受体使用和进化的回顾性分析，该分析考虑了核心受体使用，来自一名因出现 X4 株而失败马拉维若包含方案的患者。X4 马拉维若逃逸变异是由 2003 年长期存档的前病毒序列（5'-部分，包括 V3 环）与马拉维若治疗开始时循环在血浆中的主要 R5 株之间重组而成（3'-部分）。系统发育分析和 BEAST 模型强调，早期多样化的病毒准种在重新开始 HAART 和 1999 年至 2001 年之间反复进行 IL-2 循环后经历了严重的瓶颈，导致从血浆中短暂生长和存档一个高度同源的 X4 群体，并导致一个 PBMC 衍生的 R5 株在血浆中扩展。在马拉维若选择压力下，早期在 PBMC 中不再检测到的 X4 株被部分挽救，为主要循环株提供了 X4 决定簇。
