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Hepatitis B Surface Antigen Seroclearance: Immune Mechanisms, Clinical Impact, Importance for Drug Development
Issam Tout
Dimitri Loureiro
Abdellah Mansouri
Vassili Soumelis
Nathalie Boyer
Tarik Asselah
Published:April 22, 2020DOI:https://doi.org/10.1016/j.jhep.2020.04.013
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Abstract
Hepatitis B surface antigen (HBsAg) seroclearance occurs rarely in the natural history of chronic hepatitis B (CHB) infection and is associated with a reduced risk of hepatocellular carcinoma (HCC). Many factors are associated with HBsAg seroconversion, including immune, and viral factors. However, the immune mechanisms associated with HBsAg seroclearance are still difficult to elucidate.
The aim of the treatment of hepatitis B virus (HBV) infection is the seroclearance of HBsAg. Unfortunately, this goal is rarely reached with current approved treatments. Understanding HBsAg loss mechanisms appears important to achieve an HBV cure drug development. While studies from HBV animal models are giving insights on the potential immune mechanisms and interactions occurring between the immune system and HBsAg, they do not recapitulate all features of CHB in human and are subject to variability due to their complexity. In this article, we review recent studies on these immune factors, their influence on CHB progression, and HBsAg seroconversion. These data provide new insights in the development of immune therapeutic approaches to partially restore the anti-HBV immune response. Targeting HBsAg will ideally relieve the immunosuppressive effects on the immune system and help to restore anti-HBV immune responses.
Keywords
Chronic HBV infection
HBsAg seroclearance
Immune system
Interferon
Nucleos(t)ide analogues
HBV therapy
Abbreviations:
aa (amino acid), ALT (Alanine aminotransferase), anti-HBsAg (hepatitis B surface antigen antibodies), AST (Aspartate aminotransferase), AIM2 (Absent in melanoma 2), atMBC (Atypic Memory B cells), cccDNA (covalently closed circular DNA), CHB (chronic hepatitis B), CTL (Cytotoxic T cell), DC (Dendritic cells), ETV (entecavir), FDA (Food and Drug Administration), FNA (Fine needle aspiration), HBcAg (Hepatitis B core antigen), HBcrAg (Hepatitis B core-related antigen), HBeAg (Hepatitis B e antigen), HBsAg (Hepatitis B surface antigen), HBV (hepatitis B virus), HBV SVPs (Hepatitis B virus sub-viral particles), HCC (hepatocellular carcinoma), hNTCP (human sodium taurocholate cotransporting polypeptide), IFN-α (interferon alpha), IL (Interleukin), IRF7 (Interferon regulatory factor 7), JNK (c-Jun N-terminal protein kinase), KC (Kupffer cells), LAG-3 (Lymphocyte-activation gene 3), L-HBsAg (Large Hepatitis B surface antigen), LSEC (Liver sinusoidal endothelial cells), MAIT (mucosal associated invariant T cells), MDSC (Myeloid-derived suppressor cells), M-HBsAg (Medium Hepatitis B surface antigen), mRNA (messenger RNA), MVP (Major vault protein), MyD88 (Myeloid differentiation primary response 88), NA (nucleoside analogue), NAP (Nucleic Acid Polymer), NK cells (Natural Killer cells), ORF (open reading frames), PD-1 (Programmed cell death protein 1), PEG-IFN (pegylated interferon), pgRNA (pregenomic RNA), PRR (Pattern recognition receptor), rcDNA (relaxed circular DNA), S-HBsAg (Small Hepatitis B surface antigen), siRNA (small interfering RNA), TAF (tenofovir alafenamide), T-bet (T-box protein expressed in T cells), TDF (tenofovir disoproxil fumarate), TFH (T Follicular Helper cell), TFV (tenofovir), Tim-3 (T-cell immunoglobulin and mucin-domain containing-3), TLR (toll-like receptor), TNF-α (Tumor necrosis factor alpha), Treg (Regulatory T cells)
Key Points
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HBsAg seroclearance is a rare event in the natural history of CHB.
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HBsAg seroclearance is associated with a reduced risk of HCC.
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HBsAg contributes to the deregulation of both innate and adaptive immune cells.
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The decrease of HBsAg can potentially restore anti-HBV immune responses.
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Combination of antivirals and immune therapy is crucial for drug development. |
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