人类免疫缺陷病毒 1 型分离物对小分子 CCR5 抑制剂的耐药性可能涉及 gp120 和 gp41 中的序列变化。
Resistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41.
机构信息
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
出版信息
Virology. 2011 Apr 25;413(1):47-59. doi: 10.1016/j.virol.2010.12.052. Epub 2011 Feb 26.
Abstract
Here, we describe the genetic pathways taken by a human immunodeficiency virus type 1 (HIV-1) isolate, D101.12, to become resistant to the small molecule CCR5 inhibitor, vicriviroc (VCV), in vitro. Resistant D101.12 variants contained at least one substitution in the gp120 V3 region (H308P), plus one of two patterns of gp41 sequence changes involving the fusion peptide (FP) and a downstream residue: G514V+V535M or M518V+F519L+V535M. Studies of Env-chimeric and point-substituted viruses in peripheral blood mononuclear cells (PBMC) and TZM-bl cells showed that resistance can arise from the cooperative action of gp120 and gp41 changes, while retaining CCR5 usage. Modeling the VCV inhibition data from the two cell types suggests that D101.12 discriminates between high- and low-VCV affinity forms of CCR5 less than D1/85.16, a resistant virus with three FP substitutions.
摘要
在这里，我们描述了人类免疫缺陷病毒 1 型（HIV-1）分离株 D101.12 在体外对小分子 CCR5 抑制剂维立西罗（VCV）产生耐药性的遗传途径。耐药的 D101.12 变体在 gp120 V3 区至少含有一个取代（H308P），加上 gp41 序列变化的两种模式之一，涉及融合肽（FP）和下游残基：G514V+V535M 或 M518V+F519L+V535M。在外周血单核细胞（PBMC）和 TZM-bl 细胞中对 Env-嵌合和定点取代病毒的研究表明，耐药性可以由 gp120 和 gp41 变化的协同作用引起，同时保留 CCR5 的使用。对来自两种细胞类型的 VCV 抑制数据进行建模表明，D101.12 对 CCR5 的高亲和力和低亲和力形式的区分能力低于 D1/85.16，后者是一种具有三个 FP 取代的耐药病毒。
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