Gramberg Thomas, Zhu Tuofu, Chaipan Chawaree, Marzi Andrea, Liu Huanliang, Wegele Anja, Andrus Thomas, Hofmann Heike, Pöhlmann Stefan
Institute for Clinical and Molecular Virology, University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Virology. 2006 Apr 10;347(2):354-63. doi: 10.1016/j.virol.2005.11.033. Epub 2006 Jan 18.
The lectins DC-SIGN and DC-SIGNR augment infection by human immunodeficiency virus (HIV), Ebolavirus (EBOV) and other pathogens. The neck domain of these proteins drives multimerization, which is believed to be required for efficient recognition of multivalent ligands. The neck domain of DC-SIGN consists of seven sequence repeats with rare variations. In contrast, the DC-SIGNR neck domain is polymorphic and, in addition to the wild type (wt) allele with seven repeat units, allelic forms with five and six sequence repeats are frequently found. A potential association of the DC-SIGNR genotype and risk of HIV-1 infection is currently under debate. Therefore, we investigated if DC-SIGNR alleles with five and six repeat units exhibit defects in pathogen capture. Here, we show that wt DC-SIGNR and patient derived alleles with five and six repeats bind viral glycoproteins, augment viral infection and tetramerize with comparable efficiency. Moreover, coexpression of wt DC-SIGNR and alleles with five repeats did not decrease the interaction with pathogens compared to expression of each allele alone, suggesting that potential formation of hetero-oligomers does not appreciably reduce pathogen binding, at least under conditions of high expression. Thus, our results do not provide evidence for diminished pathogen capture by DC-SIGNR alleles with five and six repeat units. Albeit, we cannot exclude that subtle, but in vivo relevant differences remained undetected, our analysis suggests that indirect mechanisms could account for the association of polymorphisms in the DC-SIGNR neck region with reduced risk of HIV-1 infection.
凝集素DC-SIGN和DC-SIGNR可增强人类免疫缺陷病毒（HIV）、埃博拉病毒（EBOV）及其他病原体的感染。这些蛋白的颈部结构域驱动多聚化，而多聚化被认为是有效识别多价配体所必需的。DC-SIGN的颈部结构域由七个序列重复组成，变异较少。相比之下，DC-SIGNR的颈部结构域具有多态性，除了具有七个重复单元的野生型（wt）等位基因外，还经常发现具有五个和六个序列重复的等位基因形式。目前，DC-SIGNR基因型与HIV-1感染风险之间的潜在关联仍存在争议。因此，我们研究了具有五个和六个重复单元的DC-SIGNR等位基因在病原体捕获方面是否存在缺陷。在此，我们表明wt DC-SIGNR以及来自患者的具有五个和六个重复单元的等位基因能够结合病毒糖蛋白，以相当的效率增强病毒感染并形成四聚体。此外，与单独表达每个等位基因相比，wt DC-SIGNR与具有五个重复单元的等位基因共表达时，与病原体的相互作用并未减弱，这表明至少在高表达条件下，异源寡聚体的潜在形成不会明显降低病原体结合。因此，我们的结果并未提供证据表明具有五个和六个重复单元的DC-SIGNR等位基因在病原体捕获方面有所减弱。尽管我们不能排除存在未被检测到的细微但在体内相关的差异，但我们的分析表明，间接机制可能解释了DC-SIGNR颈部区域多态性与HIV-1感染风险降低之间的关联。
