Synthesis and Immunological Evaluation of Pentamannose-Based HIV-1 Vaccine Candidates
Synthesis and Immunological Evaluation of Pentamannose-Based HIV-1 Vaccine Candidates
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基于五甘露糖的 HIV-1 候选疫苗的合成和免疫学评价
DOI：
10.1021/acs.bioconjchem.2c00079
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发表时间：
2022-05-18
影响因子：
4.7
通讯作者：
Ye，Xin-Shan
中科院分区：
文献类型：
--
作者：
Liu，Chang-Cheng;Huo，Chang-Xin;Ye，Xin-Shan
人类免疫缺陷病毒1（HIV-1）包膜蛋白的密集糖基化和三聚体构象限制了一些细胞聚糖加工酶的可及性，最终在包膜刺突上形成高甘露糖型N连接聚糖，其中Man5GlcNAc2结构占据一定比例。 Man5GlcNAc2 聚糖构成了一些有效的广泛中和抗体的结合位点，一些可以结合 Man5GlcNAc2 的凝集素显示出 HIV 中和活性。因此，Man5GlcNAc2是HIV-1疫苗开发的潜在靶点。在此，开发了一种高度收敛且有效的策略来合成Man5及其单氟修饰、三氟修饰和S连接类似物。我们将这些半抗原与载体蛋白 CRM197 偶联，并评估了糖缀合物在小鼠中的免疫原性。血清学测定表明，天然Man5缀合物未能在体内诱导Man5特异性抗体，而修饰的类似物缀合物诱导更强的抗体反应。然而，这些抗体不能结合天然 gp120 抗原。这些结果表明，免疫耐受机制抑制了对Man5相关结构的免疫反应，并且合成的糖缀合物上的聚糖表位的构象与gp120上的天然聚糖表位的构象不同。
Dense glycosylation and the trimeric conformation of the human immunodeficiency virus-1 (HIV-1) envelope protein limit the accessibility of some cellular glycan processing enzymes and end up with high-mannose-typeN-linked glycans on the envelope spike, among which the Man5GlcNAc2structure occupies a certain proportion. The Man5GlcNAc2glycan composes the binding sites of some potent broadly neutralizing antibodies, and some lectins that can bind Man5GlcNAc2show HIV-neutralizing activity. Therefore, Man5GlcNAc2is a potential target for HIV-1 vaccine development. Herein, a highly convergent and effective strategy was developed for the synthesis of Man5and its monofluoro-modified, trifluoro-modified, andS-linked analogues. We coupled these haptens to carrier protein CRM197 and evaluated the immunogenicity of the glycoconjugates in mice. The serological assays showed that the native Man5conjugates failed to induce Man5-specific antibodiesin vivo, while the modified analogue conjugates induced stronger antibody responses. However, these antibodies could not bind the native gp120 antigen. These results demonstrated that the immune tolerance mechanism suppressed the immune responses to Man5-related structures and the conformation of glycan epitopes on the synthesized glycoconjugates was distinct from that of native glycan epitopes on gp120.