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)是已知的导致免疫抑制的三种主要人类病原体。免疫反应的下调是一种免疫抑制状态，这给了感染病原体逃避免疫监视的机会，从而使它们在宿主内生存的机会最大化，根据需要进行复制和传播。病毒感染引起的全身性免疫抑制通常与无关的病毒和/或细菌病原体的继发感染有关，因此是一个严重的临床问题。在人类中，巨细胞病毒感染可导致正常个体的组织损伤，并可能在免疫系统不成熟或受损的个体中导致严重疾病，甚至死亡，如新生儿、艾滋病患者、移植受者和正在接受化疗的患者。在后一组患者中发生的严重并发症是由于预先存在的免疫抑制和病毒诱导的免疫抑制的共同作用，这往往会导致严重的继发性机会性感染。然而，在移植受者中，在没有继发感染的情况下，CMV诱导的免疫抑制可能是有益的，并与改善移植结果有关。目前这项工作的中心目标是研究巨细胞病毒诱导免疫抑制的细胞和病毒机制。这些研究将加深我们对病毒干扰宿主免疫反应的理解，从而有助于理解人类巨细胞病毒感染的发病机制，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的见解。

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.