title: Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection.
abstract: 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.
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ejuan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kosinska
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany ; Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Möller
authors.affiliation: Institute for Medical Virology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Seiz
authors.affiliation: Institute for Medical Virology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Glebe
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Baoju
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yang
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017919:Hepatitis B Virus, Woodchuck / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008392:Marmota; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology / Q000493:pharmacokinetics; D014765:Viral Vaccines / Q000276:immunology / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA; D014765:Viral Vaccines; C413685:entecavir; D006147:Guanine