UCL Discovery

Abstract

Chronic hepatitis B (CHB) results from a complex interaction between a replicating non-cytopathic virus and an impaired antiviral host immune response. The Programmed Cell Death (PD-1) pathway is an immunoinhibitory T-cell pathway implicated in virus-specific T-cell dysfunction in several chronic viral infections. The role of the PD-1 pathway in the immunopathogenesis of chronic hepatitis B was investigated through several different approaches. Firstly, longitudinal changes in PD-1 expression in patients with CHB undergoing oral antiviral therapy was investigated. A direct correlation between viral load and PD-1 expression on virus-specific CD8+T-cells was observed in this patient cohort, and treatment induced suppression of viraemia resulted in a significant decrease in PD-1 expression on virus-specific CD8+ T-cells with a decrease in HBV-DNA and improvement in virus specific T-cell reactivity. Secondly, through the employment of a purposely-designed in vitro cell co-culture model of Hepatitis B virus infection the interactions between HBV-producing hepatoma cells (target cells) and HBV-specific CD8+ T-cells (effector cells) was investigated. This model provided evidence that both cytolytic and non-cytolytic CD8+ T-cell effector functions are important in effective control of viral replication, and blockade of the PD-1 pathway distorts the balance between these differential effector functions in vitro. Finally through the transfection of a human hepatoma cell line with hepatitis B virus (HBV) and the analysis of hepatoma cell lines that differentially express HBV these studies demonstrate that the Hepatitis B virus itself upregulates PDL1 expression on infected hepatocytes in vitro and in doing so, are able to alter the balance between cytolytic and non-cytolytic CD8+ T-cell effector functions favouring chronicity of infection. Manipulation of the PD-1 pathway may be a possible mechanism to improve virus-specific host immune responses and allow control of HBV infection. However, these immunotherapeutic strategies require careful application as there is a potential risk of immune-mediated host tissue damage.

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