Institute for Virology, University Medical Center and Center for Immunotherapy of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
Viruses. 2018 Dec 6;10(12):693. doi: 10.3390/v10120693.
Human Cytomegalovirus (hCMV), which is the prototype member of the β-subfamily of the herpesvirus family, is a pathogen of high clinical relevance in recipients of hematopoietic cell transplantation (HCT). hCMV causes multiple-organ disease and interstitial pneumonia in particular upon infection during the immunocompromised period before hematopoietic reconstitution restores antiviral immunity. Clinical investigation of pathomechanisms and of strategies for an immune intervention aimed at restoring antiviral immunity earlier than by hematopoietic reconstitution are limited in patients to observational studies mainly because of ethical issues including the imperative medical indication for chemotherapy with antivirals. Aimed experimental studies into mechanisms, thus, require animal models that match the human disease as close as possible. Any model for hCMV disease is, however, constrained by the strict host-species specificity of CMVs that prevents the study of hCMV in any animal model including non-human primates. During eons of co-speciation, CMVs each have evolved a set of "private genes" in adaptation to their specific mammalian host including genes that have no homolog in the CMV virus species of any other host species. With a focus on the mouse model of CD8 T cell-based immunotherapy of CMV disease after experimental HCT and infection with murine CMV (mCMV), we review data in support of the phenomenon of "biological convergence" in virus-host adaptation. This includes shared fundamental principles of immune control and immune evasion, which allows us to at least make reasoned predictions from the animal model as an experimental "proof of concept." The aim of a model primarily is to define questions to be addressed by clinical investigation for verification, falsification, or modification and the results can then give feedback to refine the experimental model for research from "bedside to bench".
人巨细胞病毒（hCMV）是疱疹病毒家族β亚科的原型成员，是造血细胞移植（HCT）受者中具有高度临床相关性的病原体。hCMV 在造血重建恢复抗病毒免疫之前的免疫抑制期感染时，特别是会导致多器官疾病和间质性肺炎。由于包括化疗加抗病毒治疗的强制性医学指征在内的伦理问题，患者中针对发病机制和旨在比造血重建更早恢复抗病毒免疫的免疫干预策略的临床研究仅限于观察性研究。因此，针对机制的实验研究需要尽可能匹配人类疾病的动物模型。然而，任何 hCMV 疾病的模型都受到 CMVs 的严格宿主种特异性的限制，这阻止了在包括非人类灵长类动物在内的任何动物模型中研究 hCMV。在共同进化的漫长岁月中，CMVs 各自为适应其特定的哺乳动物宿主进化出了一套“私有基因”，包括在任何其他宿主物种的 CMV 病毒物种中没有同源物的基因。我们重点关注实验性 HCT 后和感染鼠巨细胞病毒（mCMV）后 CD8 T 细胞为基础的 CMV 疾病免疫治疗的小鼠模型，综述支持病毒-宿主适应中“生物趋同”现象的数据。这包括免疫控制和免疫逃逸的共同基本原则，这使我们能够至少根据动物模型进行合理预测，作为实验“概念验证”。模型的主要目的是定义需要通过临床研究来验证、证伪或修改的问题，然后结果可以反馈回来，以改进从“床边到实验台”的研究的实验模型。
