来自雪花莲和玉米的密切相关凝集素的甘露寡糖特异性的差异强烈决定了它们最终的抗 HIV 活性。
Differences in the mannose oligomer specificities of the closely related lectins from Galanthus nivalis and Zea mays strongly determine their eventual anti-HIV activity.
机构信息
Rega Institute for Medical Research, K,U,Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
出版信息
Retrovirology. 2011 Feb 11;8(1):10. doi: 10.1186/1742-4690-8-10.
BACKGROUND
In a recent report, the carbohydrate-binding specificities of the plant lectins Galanthus nivalis (GNA) and the closely related lectin from Zea mays (GNAmaize) were determined by glycan array analysis and indicated that GNAmaize recognizes complex-type N-glycans whereas GNA has specificity towards high-mannose-type glycans. Both lectins are tetrameric proteins sharing 64% sequence similarity.
RESULTS
GNAmaize appeared to be ~20- to 100-fold less inhibitory than GNA against HIV infection, syncytia formation between persistently HIV-1-infected HuT-78 cells and uninfected CD4+ T-lymphocyte SupT1 cells, HIV-1 capture by DC-SIGN and subsequent transmission of DC-SIGN-captured virions to uninfected CD4+ T-lymphocyte cells. In contrast to GNA, which preferentially selects for virus strains with deleted high-mannose-type glycans on gp120, prolonged exposure of HIV-1 to dose-escalating concentrations of GNAmaize selected for mutant virus strains in which one complex-type glycan of gp120 was deleted. Surface Plasmon Resonance (SPR) analysis revealed that GNA and GNAmaize interact with HIV IIIB gp120 with affinity constants (KD) of 0.33 nM and 34 nM, respectively. Whereas immobilized GNA specifically binds mannose oligomers, GNAmaize selectively binds complex-type GlcNAcβ1,2Man oligomers. Also, epitope mapping experiments revealed that GNA and the mannose-specific mAb 2G12 can independently bind from GNAmaize to gp120, whereas GNAmaize cannot efficiently bind to gp120 that contained prebound PHA-E (GlcNAcβ1,2man specific) or SNA (NeuAcα2,6X specific).
CONCLUSION
The markedly reduced anti-HIV activity of GNAmaize compared to GNA can be explained by the profound shift in glycan recognition and the disappearance of carbohydrate-binding sites in GNAmaize that have high affinity for mannose oligomers. These findings underscore the need for mannose oligomer recognition of therapeutics to be endowed with anti-HIV activity and that mannose, but not complex-type glycan binding of chemotherapeutics to gp120, may result in a pronounced neutralizing activity against the virus.
背景
在最近的一份报告中，通过聚糖阵列分析确定了植物凝集素雪花莲（Galanthus nivalis，GNA）和与之密切相关的来自玉米（GNAmaize）的凝集素的碳水化合物结合特异性，表明 GNAmaize 识别复杂型 N-糖链，而 GNA 则具有对高甘露糖型糖链的特异性。两种凝集素均为具有 64%序列相似性的四聚体蛋白。
结果
与 GNA 相比，GNAmaize 对 HIV 感染、持续感染 HIV-1 的 HuT-78 细胞与未感染 CD4+T 淋巴细胞 SupT1 细胞之间的合胞体形成、DC-SIGN 捕获 HIV-1 以及随后将 DC-SIGN 捕获的病毒颗粒传递给未感染的 CD4+T 淋巴细胞的抑制作用低 20-100 倍。与 GNA 不同，GNA 优先选择 gp120 上缺失高甘露糖型糖的病毒株，而 HIV-1 长时间暴露于递增浓度的 GNAmaize 会选择 gp120 上一个复杂型糖被删除的突变病毒株。表面等离子体共振（SPR）分析表明，GNA 和 GNAmaize 与 HIV IIIB gp120 的亲和力常数（KD）分别为 0.33 nM 和 34 nM。固定化 GNA 特异性结合甘露寡糖，而 GNAmaize 选择性结合复杂型 GlcNAcβ1,2Man 寡糖。此外，表位作图实验表明，GNA 和甘露糖特异性 mAb 2G12 可以分别与 GNAmaize 一起从 gp120 上独立结合，而 GNAmaize 不能有效地与预先结合 PHA-E（GlcNAcβ1,2man 特异性）或 SNA（NeuAcα2,6X 特异性）的 gp120 结合。
结论
与 GNA 相比，GNAmaize 抗 HIV 活性明显降低，这可以解释为聚糖识别的深刻转变，以及 GNAmaize 中对甘露寡糖具有高亲和力的碳水化合物结合位点的消失。这些发现强调了赋予治疗剂抗 HIV 活性需要识别甘露寡糖的必要性，并且甘露糖，而不是化学治疗剂与 gp120 的复杂型糖结合，可能导致对病毒的明显中和活性。
Zotero 插件