乙肝病毒慢性感染仍然是世界性公共健康问题。我们在早先研究中设计构建了一种外源性抗原重组的乙肝病毒(rHBV)，提出基于外源抗原T细胞应答的免疫治疗概念。本项课题中，我们拟应用腺病毒载体的rHBV病毒（rAd/rHBV），发展基于基因治疗和主动免疫的双重策略。rAd/rHBV感染野生乙肝病毒已感染的肝细胞、互补复制产生子代rHBV，在病毒学机制上，rAd/rHBV能够有效竞争并抑制野生乙肝病毒复制，释放的病毒粒子进一步感染其它肝细胞，放大非增殖性腺病毒载体的治疗效应；疫苗策略上，互补复制的rHBV高效表达外源抗原，由于rHBV和野生乙肝病毒具有相同的复制机制，外源抗原激活的功能T细胞应答将最终清除野生病毒的感染。我们将通过体内和体外实验对rAd/rHBV的病毒和免疫学特征进行分析，同时，我们拟建立HLA-A2人源化背景的可复制乙肝转基因小鼠模型，对rAd/rHBV治疗策略进行系统评价。

Hepatitis B virus (HBV) remains a major cause of human disease worldwide. We previously proposed a new concept of therapeutic vaccination against chronic HBV infection, based on a recombinant HBV (rHBV) carrying a sequence encoding foreign antigenic epitopes. In the current study, practically, we plan to make the advantage of adenovirus vector(s) to deliver rHBV (rAd/rHBV), aiming to cure HBV infection by double regulations at the gene therapy and active immunization levels. rHBV would be efficiently delivered by the adenovirus vector and only self-maintain in hepatocytes already infected by HBV through capsid complementation. Virologically, rAd/rHBV is supposed to have an advantage in the viral replication which could effectively suppress wild type HBV (wtHBV) infection. Released progeny rHBV may infect more hepatocytes that expands the therapeutic effect. Moreover, for vaccination purpose, capsid-rescued rHBV replication leads to a productive expression of the foreign antigenic epitopes which in turn activate vigorous T cell responses in situ. Since rHBV co-maintains with wtHBV and shares the same replicative cycle, rHBV-based T cell responses might exert antiviral functions and finally eliminate the wtHBV infection. In the study, a comprehensive analysis will be preformed in vivo and in vitro to characterize rAd/rHBV virologically and immunologically. A surrogate model of HBV transgenic mouse with MHC-I humanized background would be established for a systematical evaluation of the rAd/rHBV-based therapeutic strategy.