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  • Review Article
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Immunology of hepatitis B virus and hepatitis C virus infection

Key Points

  • Hepatitis B virus (HBV) and hepatitis C virus (HCV) are both parenterally transmitted enveloped viruses that induce acute and chronic necroinflammatory liver disease. HBV is a partially double-stranded DNA virus and a member of the hepadnaviridae family, whereas HCV is a positive-stranded RNA virus and constitutes a separate genus in the flaviviridae family.

  • HBV and HCV have a narrow host range, which is limited to humans and chimpanzees. Humans are the main natural host for HBV (a single indigenous HBV strain has been identified in chimpanzees in West Africa) and the only natural host for HCV.

  • The most common cause of chronic hepatitis B is vertical transmission from mother to neonate. Vertical transmission is not common for hepatitis C.

  • More than 90% of those individuals who acquire HBV infection as adults, but only 20–40% of those who acquire HCV infection as adults spontaneously recover from all clinical symptoms.

  • Studies of experimentally infected chimpanzees showed that HBV does not induce any detectable changes in the expression of intrahepatic genes in the first weeks of infection. By contrast, HCV upregulates the expression of many intrahepatic genes early after infection.

  • Hepatocytes in which HBV is replicating can be removed by cytotoxic mechanisms or cured by cytokine-mediated, non-cytolytic mechanisms, as shown in transgenic mice (by adoptive transfer of HBV-specific, interferon-γ (IFN-γ)-secreting T cells) and in chimpanzees (by a temporal relationship between HBV clearance and upregulation of intrahepatic IFN-γ expression in the early phase of HBV infection). A reduction in HCV titre at the time of intrahepatic IFN-γ expression has also been shown in HCV infection.

  • Humoral responses in HBV infection are important. HBV core antigen (HBcAg)-specific IgM is an early marker of infection, and the appearance of HBV e antigen (HBeAg)-specific antibodies indicates a reduction in viral titre in chronically infected patients. HBcAg- and HBV surface antigen (HBsAg)-specific IgG persist for life in recovered patients. By contrast, the appearance of HCV-specific antibodies is much more variable: no antibodies develop early after infection, and in some cases, they might not develop at all. HCV-specific antibody titres might decrease to undetectable levels 10–20 years after recovery.

  • Trace amounts of HBV persist after clinical recovery and are controlled by HBV-specific humoral and cellular immune responses. Whether trace amounts of HCV persist long-term after clinical recovery is controversial and requires studies of large patient cohorts.

  • HBV-specific immunity is observed in all clinically recovered patients and is mediated by neutralizing antibodies and T cells. HCV-specific immunity has been described for some, but not all, chimpanzees that recover from an experimental infection, and it is mediated by T cells.

  • HBV- and HCV-specific T-cell responses contribute not only to viral clearance and clinical recovery but also to immune-mediated acute and chronic liver disease.

  • Spontaneous viral clearance, generation of HBsAg-specific-antibody and resolution of disease occurs in 2% of patients with chronic hepatitis B each year, and it is temporally correlated with the appearance of HBV-specific T cells in the blood. By contrast, there is no spontaneous viral clearance in patients with chronic hepatitis C.

Abstract

More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus–host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.

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Figure 1: Genomic structure and translated proteins of HBV and HCV.
Figure 2: Putative life cycle of HBV and HCV.
Figure 3: Clinical and virological course of acute infection with HBV or HCV.
Figure 4: Candidate mechanisms of HCV interference with the immune system.

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Correspondence to Barbara Rehermann.

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Glossary

NECROINFLAMMATORY

A state in which there is morphological evidence of infiltration of inflammatory cells and necrosis of parenchymal cells.

PROTECTIVE IMMUNITY

The immune responses of individuals who have recovered from a primary infection and, on re-exposure to the pathogen, are protected from developing severe disease and chronic infection. Protective immunity can be sterilizing if it protects from a productive infection.

PSEUDOTYPE PARTICLE

A viral particle containing the genome of one virus in the envelope of another virus.

HEPADNAVIRIDAE

A family of hepatotropic DNA viruses, which contain double-stranded DNA genomes and causes hepatitis in humans and animals. Hepadnaviruses have very small genomes of relaxed circular, partially double-stranded DNA. They replicate through an RNA intermediate, which they translate back into DNA using reverse transcriptase. Hepadnaviruses include hepatitis B virus, duck hepatitis virus, heron hepatitis B virus, ground squirrel hepatitis virus and woodchuck hepatitis virus.

FLAVIVIRIDAE

A family of related positive-strand RNA viruses, which consists of three genera: flaviviruses, pestiviruses and hepaciviruses. Flaviviridae replicate by synthesis of a minus-strand RNA intermediate. Dengue virus, bovine viral diarrhoea virus and hepatitis C virus are examples from the three genera.

NUCLEOCAPSID

A nucleic acid and its surrounding protein coat (or capsid). The nucleocapsid forms the basic structural unit of the virion. Depending on the virus, the nucleocapsid might be a naked core or be surrounded by a membranous envelope.

COVALENTLY CLOSED CIRCULAR DNA

(cccDNA). The double-stranded cccDNA of HBV is the transcriptional template of HBV in the nucleus of infected cells.

INTERNAL RIBOSOMAL ENTRY SITE

(IRES). A well-defined and highly conserved secondary structure located in the 5′ untranslated region of some viral and cellular mRNAs. It mediates the translation initiation of the viral message by a 5′-cap-independent mechanism.

HBV e ANTIGEN

(Hepatitis B virus e antigen, HBeAg). HBeAg is derived from the pre-core polypeptide, which together with the core polypeptide, is encoded by the nucleocapsid open reading frame. After removal of the amino-terminal 29 amino acids of the pre-core polypeptide in the endoplasmic reticulum and trimming of the carboxyl terminus, the remaining polypeptide is secreted from infected cells as HBeAg. Neither pre-core polypeptide nor secreted HBeAg are required for HBV replication.

ALANINE AMINOTRANSFERASE

(ALT). ALT is an intracellular enzyme that transfers amino groups from L-alanine to 2-ketoglutarate or from L-glutamic acid to pyruvate. It is released into the bloodstream when hepatocytes are damaged or die. The serum ALT level (upper limit of normal is 25–40 international units per litre, depending on the laboratory) is therefore an indicator of hepatocyte injury in acute and chronic hepatitis.

EUKARYOTIC TRANSLATION INITIATION FACTOR 2α

(EIF2α). A mediator of translation initiation. Phosphorylation of EIF2α by the interferon-inducible double-stranded RNA-dependent protein kinase inhibits translation and thereby indirectly inhibits viral replication.

COMPOUND GENOTYPE

A combination of two or more genotypes at loci encoding functionally related molecules.

STEM LOOP

A hairpin structure that is formed by a single-stranded nucleic acid molecule when the ends of the molecule form a double helix (stem) based on complementary sequences and the central region remains single stranded and therefore forms a loop.

EFFECTOR MEMORY CELL PHENOTYPE

Phenotype of terminally differentiated T cells. These cells lack lymph-node homing receptors but express receptors that enable them to home to inflamed tissues. Effector memory cells contain perforin and can exert immediate effector functions without the need for further differentiation.

QUASISPECIES

A distribution of non-identical but closely related viral genomes. The entire distribution forms an organized cooperative structure, which functions as (quasi) a single unit (species).

THALASSAEMIC

An individual suffering from thalassaemia, an inherited disorder of haemoglobin metabolism that results in reduced or absent production of one or more globin chains.

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Rehermann, B., Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5, 215–229 (2005). https://doi.org/10.1038/nri1573

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