Abstract

The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.

Highlights

  • Accepted: 11 June 2021hepatitis B virus (HBV) is a small hepatotropic DNA virus where an envelope is formed by a lipid bilayer with the small, middle, and large size surface antigens (S-HBsAg, M-HBsAg, and L-HBsAg) embedded as transmembrane proteins [1,2]

  • Many studies describe the frequency of HBV mutations; a good example is a recent large-scale analysis of HBV genome sequences (n = 6479, genotypes A–H) in which they report that immune escape mutations were present in 10.7% of the sequences

  • During chronic hepatitis B (CHB), HBV persistence is due to the accumulation of closed circular DNA (cccDNA) in infected cells leading to the viral RNA transcription keeping up [95,102]

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Summary

Introduction

HBV is a small hepatotropic DNA virus where an envelope is formed by a lipid bilayer with the small, middle, and large size surface antigens (S-HBsAg, M-HBsAg, and L-HBsAg) embedded as transmembrane proteins [1,2]. The viral genome consists of a 3.2 kb relaxed circular DNA (rcDNA) molecule It contains four open reading frames (ORFs) encoding for polymerase (P), surface (S), precore/core (C), and X (Figures 1b and 2) [5]. Kilobase; RNA; HBcAg, HBV core antigen; HBVPol, produce the viral proteins. S1 region, which overlaps with nucleotides encoding the spacer domain of the HBVPol, which is relatively adaptable to non-synonymous mutations. The accumulation of these variants provides flexibility for conformational structural changes and responds to immune selective pressure [10,11]

HBV Replicative
HBV Genotypes and Variants
Clinical Relevance of HBV Diversity during Infection
Drug-Resistant Variants
HBV-Related HCC
Natural History of the HBV Infection
Acute Hepatitis B
Chronic Hepatitis B
Immune Response to HBV in the Evolution of the Infection
Response in AHB Infection
Response in CHB Infection
T cells are induced exhausted
Acute Liver Failure in HBV Infection
Liver Failure in Acute Infection
Acute-on-Chronic Hepatitis B Liver Failure
Viral Factors in ACLF
Sensing and Response to HBV
Viral Epitopes
Immune Escape Mutations and Diagnosis Failure
HBcAg and HBeAg
The Role of TLRs
10. Interferon Response
11. HBV Interference against the Antiviral Activity
Findings
12. Conclusions
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