Enhancing Virus-Specific Immunity In Vivo by Combining Therapeutic Vaccination and PD-L1 Blockade in Chronic Hepadnaviral Infection

PLoS Pathogens

Dongliang Yang¹  Mengji Lu¹  Inga Möller²  Dieter Glebe³  Baoju Wang³  Xiaoyong Zhang⁴  Weimin Wu⁴  Pia Seiz⁴  Anna Kosinska⁴  Zhiyong Ma⁴  Jia Liu⁴  Ejuan Zhang⁴  Michael Roggendorf⁴ 

[1] Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China;Institute for Medical Virology, Justus-Liebig University Giessen, Giessen, Germany;Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany

关键词: T cells;    Cytotoxic T cells;    Antibodies;    DNA vaccination;    Vaccination;    immunization;    DNA replication;    Antiviral therapy;    Viral load;   

DOI  :  10.1371/journal.ppat.1003856

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Hepatitis B virus (HBV) persistence is facilitated by exhaustion of CD8 T cells that express the inhibitory receptor programmed cell death-1 (PD-1). Improvement of the HBV-specific T cell function has been obtained in vitro by inhibiting the PD-1/PD-ligand 1 (PD-L1) interaction. In this study, we examined whether in vivo blockade of the PD-1 pathway enhances virus-specific T cell immunity and leads to the resolution of chronic hepadnaviral infection in the woodchuck model. The woodchuck PD-1 was first cloned, characterized, and its expression patterns on T cells from woodchucks with acute or chronic woodchuck hepatitis virus (WHV) infection were investigated. Woodchucks chronically infected with WHV received a combination therapy with nucleoside analogue entecavir (ETV), therapeutic DNA vaccination and woodchuck PD-L1 antibody treatment. The gain of T cell function and the suppression of WHV replication by this therapy were evaluated. We could show that PD-1 expression on CD8 T cells was correlated with WHV viral loads during WHV infection. ETV treatment significantly decreased PD-1 expression on CD8 T cells in chronic carriers. In vivo blockade of PD-1/PD-L1 pathway on CD8 T cells, in combination with ETV treatment and DNA vaccination, potently enhanced the function of virus-specific T cells. Moreover, the combination therapy potently suppressed WHV replication, leading to sustained immunological control of viral infection, anti-WHs antibody development and complete viral clearance in some woodchucks. Our results provide a new approach to improve T cell function in chronic hepatitis B infection, which may be used to design new immunotherapeutic strategies in patients.

【 授权许可】

CC BY