Cytomegalovirus-based vaccine vectors - the role of cytomegalovirus gH/gL/chemokine glycoprotein complexes in the vector-induced immune response

巨细胞病毒在宿主体内诱导强烈的终身效应记忆T细胞反应，但不能防止同一病毒的重复感染。T细胞对CMV基因组表达的外源抗原的应答可以使用相同的CMV载体反复诱导。这使得以巨细胞病毒为基础的载体成为抗其他病毒疫苗接种或肿瘤免疫治疗的优秀候选者。迄今为止研究的所有巨细胞病毒都表达一种病毒CC趋化因子，该趋化因子除了调节免疫功能外，还形成gH/gL/趋化因子糖蛋白进入复合物，决定病毒的细胞亲和性。当缺乏这种病毒趋化因子的恒河巨细胞病毒用于表达来自其他病毒的抗原时，观察到非典型和广泛的CD8+ T细胞对抗原的反应和清除这些病毒的非凡能力。目前尚不清楚观察到的病毒清除是否依赖于这些非典型CD8+ T细胞反应。以小鼠巨细胞病毒（MCMV）感染小鼠为模型，我们将分析MCMV CC趋化因子的缺失是否类似地影响CD8+ T细胞的反应，以及可溶性趋化因子、gH/gL/趋化因子复合物或两者是否决定CD8+ T细胞的反应。此外，我们将研究缺乏或表达CC趋化因子的MCMV疫苗载体是否表现出不同的控制异源病毒感染和肿瘤生长的能力，以及我们是否可以将免疫保护与非典型CD8+ T细胞反应联系起来。这些研究可能有助于构建HCMV载体，用于针对人类免疫缺陷病毒或丙型肝炎病毒等病毒的疫苗接种，或用于人类肿瘤的免疫治疗。此外，通过揭示修饰巨细胞病毒高免疫原性背后的机制，可能会发现通过其他疫苗接种策略引发类似T细胞反应的新方法。

Cytomegaloviruses induce strong and lifelong effector memory T cell responses in their hosts which nevertheless do not prevent repeated superinfection with the same virus. T cell responses to foreign antigens expressed from CMV genomes can repeatedly be elicited using the same CMV vector. This makes cytomegalovirus-based vectors excellent candidates for vaccination against other viruses or for the immune therapy of tumors. All cytomegaloviruses studied so far express a viral CC chemokine which, besides modulating immune functions, additionally forms a gH/gL/chemokine glycoprotein entry complex determining the viral cell tropism. When rhesus cytomegaloviruses lacking this viral chemokine were used to express antigens from other viruses, atypical and broad CD8+ T cell responses to the antigens and an extraordinary capacity to clear those viruses were observed. Currently, it is not clear whether the observed virus clearance is dependent on those atypical CD8+ T cell responses or not. Using infection of mice with murine cytomegalovirus (MCMV) as a model, we will analyse whether deletion of the MCMV CC chemokine similarly shapes the CD8+ T cell response and whether the soluble chemokine, the gH/gL/chemokine complex, or both determine the CD8+ T cell response. Additionally, we will study whether MCMV vaccine vectors lacking or expressing the CC chemokine show different capacities to control heterologous virus infections and tumor growth and whether we can correlate immune protection and atypical CD8+ T cell responses. These studies might help to build an HCMV vector for vaccination against viruses like human immunodeficiency or hepatitis C virus or for the immune therapy of human tumors. In addition, by unraveling the mechanisms behind the high immunogenicity of modified cytomegaloviruses new ways to elicit similar T cell responses by other vaccination strategies might be found.