University of Cape Town/Medical Research Council Research Group for Receptor Biology, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town Faculty of Health Sciences, Observatory, Cape Town, South Africa.
J Acquir Immune Defic Syndr. 2010 Aug;54(4):352-9. doi: 10.1097/QAI.0b013e3181e0c7b2.
The CCR5 chemokine receptor is the major coreceptor for HIV-1 and the receptor for CC-chemokines, MIP-1alpha, MIP-1beta, and regulated upon activation normal T-cell-expressed and secreted. Individuals, who are homozygous for the nonfunctional CCR5Delta32 allele, are largely resistant to HIV-1 infection. Four unique mutations that affect the amino acid sequence of CCR5 have been identified in South Africa. We have assessed the effect of these mutations on CCR5 interactions with chemokines and HIV Envelope protein. The LeuPhe mutation did not affect CCR5 expression, chemokine binding, intracellular signaling, or interaction with Envelope. The ArgGln mutant was similar to wild-type CCR5, but ligand-independent intracellular signaling suggests that it is partially constitutively active. The AspVal mutation decreased chemokine-binding affinity, chemokine-stimulated intracellular signaling, and receptor expression. It also decreased HIV Envelope-mediated cell fusion. The ArgStop mutant showed no measurable chemokine binding or signaling and no measurable expression of CCR5 at the cell surface or within the cell. Consistent with lack of cell surface expression, it did not support envelope-mediated cell fusion. These results show that South African CCR5 variants have a range of phenotypes in vitro that may reflect altered chemokine responses and susceptibility to HIV infection in individuals who carry these alleles.
趋化因子受体 CCR5 是 HIV-1 的主要辅助受体,也是 CC-趋化因子、MIP-1alpha、MIP-1beta 和调节激活正常 T 细胞表达和分泌的受体。纯合子携带无功能 CCR5Delta32 等位基因的个体对 HIV-1 感染具有很强的抵抗力。在南非已经鉴定出了影响 CCR5 氨基酸序列的四个独特突变。我们评估了这些突变对 CCR5 与趋化因子和 HIV 包膜蛋白相互作用的影响。LeuPhe 突变不影响 CCR5 的表达、趋化因子结合、细胞内信号转导或与包膜的相互作用。ArgGln 突变体与野生型 CCR5 相似,但配体非依赖性细胞内信号表明其部分组成型激活。AspVal 突变降低了趋化因子结合亲和力、趋化因子刺激的细胞内信号转导和受体表达。它还降低了 HIV 包膜介导的细胞融合。ArgStop 突变体没有可测量的趋化因子结合或信号转导,也没有可测量的 CCR5 表达在细胞表面或细胞内。由于缺乏细胞表面表达,它不支持包膜介导的细胞融合。这些结果表明,南非 CCR5 变体在体外具有一系列表型,这可能反映了携带这些等位基因的个体中趋化因子反应和对 HIV 感染易感性的改变。