Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition

Abstract

Chronic infections with human hepatitis viruses continue to be a major health burden worldwide. Despite the availability of an effective prophylactic vaccine against the hepatitis B virus (HBV) and of antiviral agents efficiently suppressing HBV replication, more than 250 million people are currently chronically infected with this hepatotropic DNA virus, and resolution of chronic hepatitis B (CHB) is rarely achieved. Moreover, coinfection with the hepatitis D virus (HDV), a human RNA satellite virus requiring the envelope proteins of HBV for productive viral spreading, substantially aggravates the disease course of CHB. The molecular mechanisms by which these viruses interact with each other and with the intrinsic innate responses of the hepatocytes are not fully understood. While HBV appears to avoid innate immune recognition, HDV elicits a strong enhancement of innate responses. Notwithstanding, such induction does not hamper HDV replication but contributes to liver inflammation and pathogenesis. Intriguingly, HDV appears to influence the ability of T cells to recognize infected hepatocytes by boosting antigen presentation. This review focuses on current knowledge regarding how these viruses can shape and counteract the intrinsic innate responses of the hepatocytes, thus affecting the immune system and pathogenesis. Understanding the distinct strategies of persistence that HBV and HDV have evolved is central for advancing the development of curative therapies.

Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis during HDV Infection

“…It even has been suggested that some innate pathways support HDV replication productivity [40], since the IFN system induces RNA-editing enzyme adenosine deaminase (ADAR), which is required for RNA editing to generate L-HDAg, and hence enables viral morphogenesis [45]. It is important to note that MDA-5-mediated production of IFN and ISG induction also contributes to a cytokine milieu that recruits professional antigen-presenting cells, and thus enables priming of functional T cells [46].…”

Immunopathogenesis of Acute Flare of Chronic Hepatitis B: With Emphasis on the Role of Cytokines and Chemokines

“…In contrast, liver damage during chronic HBV infection is mainly attributed to dysregulated activation of intrahepatic immunity leading to nonspecific hepatocyte killing [56][57][58][59]. By acquiring exhaustive phenotypes and producing less inflammatory chemokines and cytokines, it is believed that CD8+ T cells may not be the major mediator of hepatic injury.…”

“…The above findings demonstrated that dynamic interactions of the virus, and innate (including cytokines and chemokines) and adaptive immune responses contribute to the development of hepatitis B flare in patients with CHB [16,57,58,63]. In this review, we will mainly focus on the role of cytokines and chemokines.…”

“…Taking part in both innate and adaptive immunity, IFN-gamma serves as the primary activator of macrophages, and also of neutrophils and NK cells [3,57,58]. The cytokine triggers the differentiation of cytotoxic T cells proliferation, and is able to enhance the microbicidal activity by releasing other cytokines such as TNF-α, IL-1 and IL-6.…”

Mediators of liver inflammation and carcinogenesis

“…Infections with hepatitis viruses are a major trigger of chronic liver inflammation and liver disease. In this issue, Dandri et al discuss the innate immune response in viral hepatitis, its consequences for T cell recognition and how this impacts on viral persistence or clearance [8]. The authors elucidate viral strategies to manipulate and shape the immune response and therapeutic strategies that might specifically target viral evasion.…”