Host-virus interactions that define the outcome of anti-viral T cell responses: relevance to viral persistence

人巨细胞病毒（hCMV）感染通常在没有感染症状的情况下得到解决。然而，严重的hCMV疾病可发生在免疫功能低下的患者中，其疾病表现包括绒毛膜视网膜炎、间质性肺炎和肝炎。在免疫功能不成熟的儿童中，先天性感染可导致巨细胞包涵性疾病（CID）。婴儿的CID会引起严重的神经系统后遗症，导致智力迟钝、耳聋和失明。针对hCMV诱导的巨细胞包涵性疾病的疫苗接种已被指定为一级（最有利），因为预测它可以挽救生命并预防终身残疾。鉴于CD8 T细胞在巨细胞病毒控制中的重要作用以及巨细胞病毒在社会中的高流行率，开发一种能够引发有效T细胞反应并形成持久记忆的疫苗将是至关重要的。我们假设mCMV已经进化出一种机制，可以产生适当的T细胞反应，参与病毒控制和持续感染的建立。本研究的中心目标是研究巨细胞病毒特异性T细胞生成过程中的细胞和病毒机制。拟议的研究将提高我们对抗病毒T细胞反应产生的理解，因此将进一步加深我们对T细胞在人类感染中的作用的理解。更重要的是，这些结果将为合理设计合适的抗病毒药物和疫苗提供关键的见解。

Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccination against hCMV induced cytomegalic inclusion disease has been designated Level I (most favourable) due to the prediction that it could save lives and prevent life-long disability. Given the essential nature of CD8 T cells in CMV control and the high prevalence of CMV in society, it will be crucial to develop a vaccine capable of eliciting an efficacious T cell response which develops lasting memory. We hypothesise that mCMV has evolved mechanisms for generating an appropriate T cell response involved in viral control and the establishment of a persistent infection. The central aim of the work in the current proposal is to investigate the cellular and viral mechanisms involved in the generation of cytomegalovirus specific T cells. The proposed studies will improve our understanding of the generation of anti-viral T cell responses and hence will be relevent to further our understanding of the role of T cells in human infection. More importantly the results will provide critical insights into the rational design of suitable antiviral drugs and vaccines.