DNA vaccines expressing soluble CD4-envelope proteins fused to C3d elicit cross-reactive neutralizing antibodies to HIV-1
DNA vaccines expressing soluble CD4-envelope proteins fused to C3d elicit cross-reactive neutralizing antibodies to HIV-1
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DOI：
10.1016/j.virol.2004.07.031
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发表时间：
2004-10-25
期刊：
影响因子：
3.7
通讯作者：
Ross, TM
中科院分区：
文献类型：
--
作者：
Bower, JF;Green, TD;Ross, TM
表达人类免疫缺陷病毒1型（HIV-1）包膜（Env）的DNA疫苗在多种动物模型中产生高滴度、持久中和抗体的效果相对较差。在这项研究中，DNA疫苗的构建表达的融合蛋白的可溶性人CD4（sCD4）和gp120亚单位的HIV-1包膜。为了增强表达的融合蛋白的免疫原性，将三个拷贝的鼠C3d（mC3d（3））添加到复合物的羧基末端。识别gp120上CD4诱导表位的单克隆抗体可有效结合sCD4-gp120或sCD4-gp120-mC3d（3）。此外，sCD4-gp120和sCD4-gp120-mC3d（3）在不存在细胞表面hCD4的情况下与表达适当辅助受体的细胞结合。用表达gp120-mC3d（3）或sCD4-gp120-mC3d（3）的DNA疫苗接种小鼠（BALB/c），可引发中和同源病毒感染的抗体。然而，使用sCD4-gp120-mC3d（3）-DNA引起中和抗体的最高滴度，其在抗hCD4抗体耗尽后持续存在。有趣的是，只有用表达sCD4-gp120-mC3d（3）的DNA接种的小鼠具有引发交叉保护性中和抗体的抗体。sCD4与HIV-1包膜的融合暴露了中和表位，当融合复合物与分子佐剂C3d偶联时，这些中和表位引发广泛的保护性免疫。(C)2004爱思唯尔公司All rights reserved.
DNA vaccines expressing the envelope (Env) of the human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, DNA vaccines were constructed to express a fusion protein of the soluble human CD4 (sCD4) and the gp120 subunit of the HIV-1 envelope. To enhance the immunogenicity of the expressed fusion protein, three copies of the murine C3d (mC3d(3)) were added to the carboxyl terminus of the complex. Monoclonal antibodies that recognize CD4-induced epitopes on gp120 efficiently bound to sCD4-gp120 or sCD4-gp120-mC3d(3). In addition, both sCD4-gp120 and sCD4-gp120-mC3d(3) bound to cells expressing appropriate coreceptors in the absence of cell surface hCD4. Mice (BALB/c) vaccinated with DNA vaccines expressing either gp120-mC3d(3) or sCD4-gp120-mC3d(3) elicited antibodies that neutralized homologous virus infection. However, the use of sCD4-gp120-mC3d(3)-DNA elicited the highest titers of neutralizing antibodies that persisted after depletion of anti-hCD4 antibodies. Interestingly, only mice vaccinated with DNA expressing sCD4-gp120-mC3d(3) had antibodies that elicited cross-protective neutralizing antibodies. The fusion of sCD4 to the HIV-1 envelope exposes neutralizing epitopes that elicit broad protective immunity when the fusion complex is coupled with the molecular adjuvant, C3d. (C) 2004 Elsevier Inc. All rights reserved.