Understanding the mechanisms of cytomegalovirus induced immunosuppression: relevance to viral immunotherapies

巨细胞病毒（CMV）、麻疹和人类免疫缺陷病毒（HIV）是已知引起免疫抑制的三种主要人类病原体。以免疫抑制状态为特征的免疫应答的下调赋予感染病原体逃避免疫监视的机会，从而最大化它们在其宿主内存活、复制和按需传播的机会。由病毒感染引起的全身免疫抑制通常与不相关的病毒和/或细菌病原体的继发感染有关，因此代表了严重的临床问题。在人类中，巨细胞病毒感染可在正常个体中引起组织损伤，并可在免疫系统不成熟或受损的个体中引起严重疾病甚至死亡，例如新生儿、AIDS患者、移植受体和接受化疗的患者。在后一组患者中发生的严重并发症是由预先存在的和病毒诱导的免疫抑制的联合作用引起的，其通常导致严重的继发性机会性感染。然而，在移植受者中，CMV诱导的免疫抑制在没有继发感染的情况下可能是有益的，并且与改善的移植结果相关。本研究的主要目的是探讨巨细胞病毒诱导免疫抑制的细胞和病毒机制。拟议的研究将提高我们对病毒干扰宿主免疫应答的理解，因此将与了解人类CMV感染的发病机制相关，更重要的是将为合理设计合适的抗病毒药物和疫苗提供重要见解。

Cytomegalovirus (CMV), measles and human immunodeficiency virus (HIV) are the three main human pathogens known to induce immunosuppression. The down-regulation of immune responses that characterizes a state of immunosuppression imparts the infecting pathogens the opportunity to escape immune surveillance and thus maximizes their chances to survive within their host, to replicate and be transmitted as required. The generalized immunosuppression caused by viral infection is often associated with secondary infections with unrelated viral and-or bacterial pathogens, and as such represents a serious clinical problem. In humans, cytomegalovirus infection can cause tissue damage in normal individuals and may cause severe disease and even mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and patients undergoing chemotherapy. The severe complications that occur in the latter group of patients result from the combined effects of pre-existing and viral induced immunosuppression that often lead to severe secondary opportunistic infections. In transplant recipients however, CMV induced immunosuppression, in the absence of secondary infections, can be beneficial and has been associated with improved transplant outcome. The central aim of the work in the current proposal is to investigate the cellular and viral mechanisms involved in cytomegalovirus induced immunosuppression. The proposed studies will improve our understanding of viral interference with host immune responses and hence will be relevant to understanding the pathogenesis of CMV infection in humans and more importantly will provide critical insights into the rational design of suitable antiviral drugs and vaccines.