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

人类巨细胞病毒(HCMV)感染通常在没有感染症状的情况下得到缓解。然而，严重的巨细胞病毒病可发生在免疫功能低下的患者中，其疾病的表现包括脉络膜视网膜炎、间质性肺炎和肝炎。在免疫功能不成熟的儿童中，先天性感染会导致巨细胞包涵体病(CID)。婴儿的CID会导致严重的神经后遗症，导致智力低下、耳聋和失明。针对巨细胞病毒引起的巨细胞包涵体病的疫苗已被指定为I级(最有利)，因为预测它可以挽救生命并防止终身残疾。鉴于CD8T细胞在CMV控制中的基本性质和CMV在社会中的高流行率，开发一种能够激发有效的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已经进化出产生适当的T细胞反应的机制，参与病毒控制和持续感染的建立。目前这项工作的中心目标是研究巨细胞病毒特异性T细胞的产生所涉及的细胞和病毒机制。建议的研究将提高我们对抗病毒T细胞反应产生的理解，因此将有助于我们进一步理解T细胞在人类感染中的作用。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.