Gray Lachlan, Sterjovski Jasminka, Churchill Melissa, Ellery Philip, Nasr Najla, Lewin Sharon R, Crowe Suzanne M, Wesselingh Steven L, Cunningham Anthony L, Gorry Paul R
Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, 3001 Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia.
Virology. 2005 Jul 5;337(2):384-98. doi: 10.1016/j.virol.2005.04.034.
The mechanisms underlying the pathogenicity of CCR5-restricted (R5) human immunodeficiency virus type-1 (HIV-1) strains are incompletely understood. Acquisition or enhancement of macrophage (M)-tropism by R5 viruses contributes to R5 HIV-1 pathogenesis. In this study, we show that M-tropic R5 viruses isolated from individuals with acquired immunodeficiency syndrome (late R5 viruses) require lower levels of CD4/CCR5 expression for entry, have decreased sensitivity to inhibition by the entry inhibitors TAK-779 and T-20, and have increased sensitivity to neutralization by the Env MAb IgG1b12 compared with non-M-tropic R5 viruses isolated from asymptomatic, immunocompetent individuals (early R5 viruses). Augmenting CCR5 expression levels on monocyte-derived macrophages via retroviral transduction led to a complete or marginal restoration of M-tropism by early R5 viruses, depending on the viral strain. Thus, reduced CD4/CCR5 dependence is a phenotype of R5 HIV-1 associated with M-tropism and late stage infection, which may affect the efficacy of HIV-1 entry inhibitors.
CCR5限制性（R5）1型人类免疫缺陷病毒（HIV-1）毒株致病的潜在机制尚未完全明确。R5病毒获得或增强巨噬细胞（M）嗜性有助于R5 HIV-1发病。在本研究中，我们发现从获得性免疫缺陷综合征患者分离出的M嗜性R5病毒（晚期R5病毒）进入细胞所需的CD4/CCR5表达水平较低，对进入抑制剂TAK-779和T-20抑制作用的敏感性降低，与从无症状、免疫功能正常个体分离出的非M嗜性R5病毒（早期R5病毒）相比，对Env单克隆抗体IgG1b12中和作用的敏感性增加。通过逆转录病毒转导提高单核细胞衍生巨噬细胞上CCR5的表达水平，可使早期R5病毒的M嗜性完全或部分恢复，具体取决于病毒株。因此，降低对CD4/CCR5的依赖性是R5 HIV-1与M嗜性及晚期感染相关的一种表型，这可能会影响HIV-1进入抑制剂的疗效。
