Department of Molecular Medicine and Virology and Gene Therapy Track, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
J Virol. 2012 Nov;86(21):11558-66. doi: 10.1128/JVI.01776-12. Epub 2012 Aug 15.
Hepatitis C virus (HCV) infection remains a serious public health problem worldwide. Treatments are limited, and no preventive vaccine is available. Toward developing an HCV vaccine, we engineered two recombinant measles viruses (MVs) expressing structural proteins from the prototypic HCV subtype 1a strain H77. One virus directs the synthesis of the HCV capsid (C) protein and envelope glycoproteins (E1 and E2), which fold properly and form a heterodimer. The other virus expresses the E1 and E2 glycoproteins separately, with each one fused to the cytoplasmic tail of the MV fusion protein. Although these hybrid glycoproteins were transported to the plasma membrane, they were not incorporated into MV particles. Immunization of MV-susceptible, genetically modified mice with either vector induced neutralizing antibodies to MV and HCV. A boost with soluble E2 protein enhanced titers of neutralizing antibody against the homologous HCV envelope. In animals primed with MV expressing properly folded HCV C-E1-E2, boosting also induced cross-neutralizating antibodies against two heterologous HCV strains. These results show that recombinant MVs retain the ability to induce MV-specific humoral immunity while also eliciting HCV neutralizing antibodies, and that anti-HCV immunity can be boosted with a single dose of purified E2 protein. The use of MV vectors could have advantages for pediatric HCV vaccination.
丙型肝炎病毒 (HCV) 感染仍然是全球严重的公共卫生问题。治疗方法有限，且尚无预防性疫苗。为了开发 HCV 疫苗，我们构建了两种表达原型 HCV 1a 亚型 H77 株结构蛋白的重组麻疹病毒 (MV)。一种病毒指导 HCV 衣壳 (C) 蛋白和包膜糖蛋白 (E1 和 E2) 的合成，这些蛋白正确折叠并形成异二聚体。另一种病毒分别表达 E1 和 E2 糖蛋白，每个蛋白与 MV 融合蛋白的细胞质尾部融合。尽管这些杂交糖蛋白被转运到质膜，但它们没有被整合到 MV 颗粒中。用任一载体免疫易感 MV 的基因修饰小鼠均可诱导针对 MV 和 HCV 的中和抗体。用可溶性 E2 蛋白加强免疫可增强针对同源 HCV 包膜的中和抗体滴度。在经表达正确折叠的 HCV C-E1-E2 的 MV 初次免疫的动物中，加强免疫还可诱导针对两种异源 HCV 株的交叉中和抗体。这些结果表明，重组 MV 保留了诱导 MV 特异性体液免疫的能力，同时还可诱发生物活性 HCV 中和抗体，并且单次剂量的纯化 E2 蛋白即可增强抗 HCV 免疫。MV 载体的使用可能对小儿 HCV 疫苗接种具有优势。
