Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Nebraska Center for Virology, School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
Sci Adv. 2023 Jan 27;9(4):eade2708. doi: 10.1126/sciadv.ade2708.
Membrane proteins expressed on the surface of enveloped viruses are conformational antigens readily recognized by B cells of the immune system. An effective vaccine would require the synthesis and delivery of these native conformational antigens in lipid membranes that preserve specific epitope structures. We have created an extracellular vesicle-based technology that allows viral membrane antigens to be selectively recruited onto the surface of WW domain-activated extracellular vesicles (WAEVs). Budding of WAEVs requires secretory carrier-associated membrane protein 3, which through its proline-proline-alanine-tyrosine motif interacts with WW domains to recruit fused viral membrane antigens onto WAEVs. Immunization with influenza and HIV viral membrane proteins displayed on WAEVs elicits production of virus-specific neutralizing antibodies and, in the case of influenza antigens, protects mice from the lethal viral infection. WAEVs thus represent a versatile platform for presenting and delivering membrane antigens as vaccines against influenza, HIV, and potentially many other viral pathogens.
包膜病毒表面表达的膜蛋白是构象抗原，可被免疫系统的 B 细胞轻易识别。有效的疫苗需要在脂质膜中合成和递呈这些天然构象抗原，以保留特定表位结构。我们创建了一种基于细胞外囊泡的技术，可将病毒膜抗原选择性募集到 WW 结构域激活的细胞外囊泡（WAEV）表面。WAEV 的出芽需要分泌载体相关膜蛋白 3，其通过脯氨酸-脯氨酸-丙氨酸-酪氨酸基序与 WW 结构域相互作用，将融合的病毒膜抗原募集到 WAEV 上。用展示在 WAEV 上的流感和 HIV 病毒膜蛋白免疫小鼠可诱导产生针对病毒的中和抗体，并且在流感抗原的情况下，可保护小鼠免受致命的病毒感染。因此，WAEV 是一种多功能平台，可作为针对流感、HIV 以及潜在许多其他病毒病原体的疫苗来展示和递呈膜抗原。
