Hepatitis Delta Virus Acts as an Immunogenic Adjuvant in Hepatitis B Virus-Infected Hepatocytes

Authors:
Christine Y.L. Tham, Janine Kah, Anthony T. Tan, ..., Marc L€utgehetmann, Maura Dandri, Antonio Bertoletti
In:
Source: Cell Rep
Publication Date: (2020)
Issue: 1 (4): 100060
Research Area:
Gastroenterology
Immunotherapy / Hematology
Cells used in publication:
Hep G2
Species: human
Tissue Origin: liver
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
HuH7
Species: human
Tissue Origin: liver
PBMC, human
Species: human
Tissue Origin: blood
Hepatocyte, human
Species: human
Tissue Origin: liver
Platform:
Nucleofector™ I/II/2b
Experiment

-  Human liver chimeric uPA/SCID/ILgR2 (USG) mice were generated by transplanting 1 million thawed human hepatocytes from one donor with haplotype HLA-A0201(Lonza) into 3 to 4 week-old mice anesthetized with isofluorane.

-  For mRNA electroporation1 3 107 activated T cells were suspended in 100ml Cell Line Nucleofector Solution V and TCR mRNA was added at 20mg.The mixture was placed in a certified cuvette and electroporated using the transduction program ‘‘X-001’’ present in the nucleofector device 2B. After electroporation, cells were resuspended in AIM-V supplemented with 10% human AB serum and 100 IU/ml IL-2 at 37°C and 5% CO2 until analysis.

Abstract

Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) to complete its infection cycle and causes severe hepatitis, with limited therapeutic options. To determine the prospect of T cell therapy in HBV/HDV co-infection, we study the impact of HDV on viral antigen processing and presentation. Using in vitro models of HBV/ HDV co-infection, we demonstrate that HDV boosts HBV epitope presentation, both in HBV/HDV co-infected and neighboring mono-HBV-infected cells through the upregulation of the antigen processing pathway mediated by IFN-b/l. Liver biopsies of HBV/HDV patients confirm this upregulation.We then validate in vitro and in a HBV/HDV preclinical mouse model that HDV infection increases the anti-HBV efficacy of T cells with engineered T cell receptors. Thus, by unveiling the effect of HDV on HBV antigen presentation, we provide a framework to better understand HBV/HDV immune pathology, and advocate the utilization of engineered HBV-specific T cells as a potential treatment for HBV/HDV co-infection.