Increased immunogenicity of human immunodeficiency virus gp120 engineered to express Galα1-3Ga1β1-4GlcNAc-R epitopes
Increased immunogenicity of human immunodeficiency virus gp120 engineered to express Galα1-3Ga1β1-4GlcNAc-R epitopes
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DOI：
10.1128/jvi.00310-06
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发表时间：
2006-07-01
影响因子：
5.4
通讯作者：
Galili, Uri
中科院分区：
文献类型：
--
作者：
Abdel-Motal, Ussama;Wang, Shixia;Galili, Uri
由人类免疫缺陷病毒（HIV）包膜糖蛋白gp 120上的多个碳水化合物链组成的聚糖屏障有助于病毒逃避中和抗体。本研究描述了一种通过用Gal α 1-3Gal β 1-4GlcNAc-R（α-gal）表位酶促取代这些糖链上的唾液酸来增加gp 120疫苗免疫原性的新方法。这些表位是天然抗Gal抗体的配体，其构成类似于人类免疫球蛋白G的1%。我们假设，由于抗体的Fc部分与抗原呈递细胞（APC）上的Fc γ受体之间的相互作用，用表达et-gal表位（gp 120（alpha gal））的gp 120接种导致体内形成具有抗Gal的免疫复合物，其靶向疫苗以供抗原呈递细胞（APC）有效摄取。这又导致疫苗有效转运至淋巴结，并通过APC有效加工和呈递gp 120免疫原性肽，以引发强的抗gp 120免疫应答。在产生抗Gal的α-1，3-半乳糖基转移酶敲除小鼠中测试了这一假设。用gp 120（alpha gal）免疫的小鼠产生的抗gp 120抗体的滴度比用相当量的gp 120免疫的小鼠中测量的滴度高> 100倍，并且有效地中和HIV。通过ELISPOT测量的T细胞应答在用gp 120（α gal）免疫的小鼠中比在用gp 120免疫的小鼠中高得多。建议gp 120（alpha gal）可以作为抗Gal介导的靶向与gp 120（alpha gal）融合的另外的疫苗接种HIV蛋白的平台，从而产生有效的预防性疫苗。
The glycan shield comprised of multiple carbohydrate chains on the human immunodeficiency virus (HIV) envelope glycoprotein gp120 helps the virus to evade neutralizing antibodies. The present study describes a novel method for increasing immunogenicity of gp120 vaccine by enzymatic replacement of sialic acid on these carbohydrate chains with Gal alpha 1-3Gal beta 1-4GlcNAc-R (alpha-gal) epitopes. These epitopes are ligands for the natural anti-Gal antibody constituting similar to 1% of immunoglobulin G in humans. We hypothesize that vaccination with gp120 expressing et-gal epitopes (gp120(alpha gal)) results in in vivo formation of immune complexes with anti-Gal, which targets vaccines for effective uptake by antigen-presenting cells (APC), due to interaction between the Fc portion of the antibody and Fc gamma receptors on APC. This in turn results in effective transport of the vaccine to lymph nodes and effective processing and presentation of gp120 immunogenic peptides by APC for eliciting a strong anti-gp120 immune response. This hypothesis was tested in alpha-1,3-galactosyltransferase knockout mice, which produce anti-Gal. Mice immunized with gp120(alpha gal) produced anti-gp120 antibodies in titers that were > 100-fold higher than those measured in mice immunized with comparable amounts of gp120 and effectively neutralized HIV. T-cell response, measured by ELISPOT, was much higher in mice immunized with gp120(alpha gal) than in mice immunized with gp120. It is suggested that gp120(alpha gal) can serve as a platform for anti-Gal-mediated targeting of additional vaccinating HIV proteins fused to gp120(alpha gal), thereby creating effective prophylactic vaccines.