Frasca Loredana, Scottà Cristiano, Del Porto Paola, Nicosia Alfredo, Pasquazzi Caterina, Versace Ilaria, Masci Anna Maria, Racioppi Luigi, Piccolella Enza
Department of Cellular and Developmental Biology, La Sapienza University, Rome, Italy.
Hepatology. 2003 Sep;38(3):653-63. doi: 10.1053/jhep.2003.50387.
An ideal strategy that leads to a vaccine aimed at controlling viral escape may be that of preventing the replication of escape mutants by eliciting a T- and B-cell repertoire directed against many viral variants. The hypervariable region 1 (HVR1) of the putative envelope 2 protein that presents B and T epitopes shown to induce protective immunity against hepatitis C virus (HCV), might be suitable for this purpose if its immunogenicity can be improved by generating mimics that induce broad, highly cross-reactive, anti-HVR1 responses. Recently we described a successful approach to select HVR1 mimics (mimotopes) incorporating the variability found in a great number of viral variants. In this report we explore whether these mimotopes, designed to mimic B-cell epitopes, also mimic helper T-cell epitopes. The first interesting observation is that mimotopes selected for their reactivity to HVR1-specific antibodies of infected patients also do express HVR1 T-cell epitopes, suggesting that similar constraints govern HVR1-specific humoral and cellular immune responses. Moreover, some HVR1 mimotopes stimulate a multispecific CD4(+) T-cell repertoire that effectively cross-reacts with HVR1 native sequences. This may significantly limit effects as a T-cell receptor (TCR) antagonist frequently exerted by natural HVR1-variants on HVR1-specific T-cell responses. In conclusion, these data lend strong support to using HVR1 mimotopes in vaccines designed to prevent replication of escape mutants.
一种旨在研发出能控制病毒逃逸的疫苗的理想策略，可能是通过引发针对多种病毒变体的T细胞和B细胞库来阻止逃逸突变体的复制。假定的包膜2蛋白的高变区1（HVR1）呈现出B细胞和T细胞表位，已证明其可诱导针对丙型肝炎病毒（HCV）的保护性免疫，如果通过生成能诱导广泛、高度交叉反应的抗HVR1反应的模拟物来提高其免疫原性，那么它可能适用于此目的。最近我们描述了一种成功的方法来选择包含大量病毒变体中发现的变异性的HVR1模拟物（模拟表位）。在本报告中，我们探讨这些旨在模拟B细胞表位的模拟表位是否也能模拟辅助性T细胞表位。第一个有趣的观察结果是，因与感染患者的HVR1特异性抗体反应性而被选择的模拟表位也确实表达HVR1 T细胞表位，这表明类似的限制因素支配着HVR1特异性体液免疫和细胞免疫反应。此外，一些HVR1模拟表位刺激多特异性CD4(+) T细胞库，该细胞库能与HVR1天然序列有效交叉反应。这可能会显著限制天然HVR1变体经常对HVR1特异性T细胞反应发挥的作为T细胞受体（TCR）拮抗剂的作用。总之，这些数据为在旨在防止逃逸突变体复制的疫苗中使用HVR1模拟表位提供了有力支持。
