Hepatitis B Virus

Abstract

Human hepatitis B virus (HBV) is the prototype member of the Hepadnaviridae family of viruses, characterised by a relaxed circular, ∼3200‐bp deoxyribonucleic acid (DNA) genome (rcDNA) with replication primarily in hepatocytes, the major parenchymal cell of the liver. HBV infections may be transient or chronic. All hepadnaviruses, including those that infect humans as well as small animal species, are similar clinically and biologically. Part of the replication strategy includes conversion of the rcDNA genome into covalently closed circular DNA (cccDNA), which is found exclusively in the nucleus of infected hepatocytes. This cccDNA acts as template for the transcription of all hepadnaviral messenger ribonucleic acids (mRNAs). One of the largest mRNAs, the pregenome, is reverse transcribed in the cytoplasm into new rcDNA. cccDNA is a highly stable molecule present as a mini chromosome with up to 10–50 copies in the nucleus of each infected hepatocyte. The stability of cccDNA, the noncytolytic nature of infection and the fact that hepatocytes constitute a self‐renewing population make chronic HBV infections difficult to treat. The natural course of chronic HBV infection consists of four phases: immune tolerance, immune clearance, immune control and reactivation and is associated with liver disease that encompasses a wide range of histological changes.

Key Concepts:

  • There are two possible outcomes of HBV infection: transient or chronic infection.

  • Transient (acute) HBV infections often spread to infect >95% of hepatocytes and can be rapidly cleared from the liver.

  • Ninety to ninety‐five percent of adults experience transient infections, whereas 30–90% of children develop chronic HBV infections.

  • Chronic HBV infection can result in liver disease including portal and lobular inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC).

  • Multiple copies of cccDNA are present in each infected hepatocyte and act as a stable reservoir for HBV infection.

  • The highly stable nature of cccDNA is the major factor in the failure of antiviral therapy during chronic HBV infection.

  • Pre‐exposure vaccination with HBV surface antigen (HBsAg) particles results in an anti‐HBs antibody response that provides immunity against HBV infection.

  • HBV remains a major worldwide problem with >360 million people with chronic infection.

Keywords: DNA genome; cccDNA; reverse transcription; transient infection; chronic infection; liver disease; hepatocellular carcinoma; vaccination; interferon‐α; antiviral drugs

Figure 1.

The structure of the hepatitis B virus (HBV) virion (a) and relaxed circular DNA (rcDNA) genome (b). (a) The HBV virion showing the viral envelope that contains the large, medium and small forms of HBV surface antigen (L‐HBs, M‐HBs and S‐HBs), the viral nucleocapsid composed of HBV core antigen (HBcAg) and containing the rcDNA genome and pol protein. (b) The inner circles represent the two strands of the HBV genome, negative and positive; the positions of the two 11‐nt direct repeats (DR1 and DR2) are indicated by boxes, and the pol protein covalently attached to the 5′ end of the negative DNA strand (5′ pol) is shown as a small circle. A short RNA is attached to the 5′ end of the positive DNA strand. In virions, the negative DNA strand is complete, whereas the positive DNA strand is less than full length, with the variable 3′ terminus. (Positive‐strand completion occurs during initiation of new rounds of infection.) The four overlapping open reading frames (ORFs) of the positive strand transcript that encode Pre Core (preC) and Core (C), Surface (PreS1, PreS2, and S), polymerase (pol) and X proteins are shown as the circular arrows in a clockwise (5′ to 3′) direction.

Figure 2.

Structure of the HBV pregenomic RNA and encapsidation signal, epsilon (ɛ) stem loop. (a) The wavy line represents the longer than genomic length pregenomic RNA, which also serves as mRNA for both the core and pol proteins. The ɛ sequence that is present at the 5′ and 3′ ends is shown as a symbolic hairpin, and the direct repeat elements DR1, DR2 and DR1* are shown as boxes. (b) The 5′ end of the HBV pregenomic RNA containing the DR1 sequence and ɛ. The HBV ɛ consists of two inverted repeats that fold into an RNA stem–loop structure with two main stems, a bulge on one side and a conserved loop at the top. The internal bulge contains a 5′‐UUC‐3′ motif that is used by pol as the template for initiation of negative strand DNA synthesis. Following initiation of DNA synthesis, the pol‐oligonucleotide translocates to the acceptor site in the 3′ copy of DR1* and primes synthesis of the negative strand of DNA by reverse transcription (Wang and Seeger, ).

Figure 3.

Hepatitis B virus (HBV) infection in a single cell. Noninfectious surface antigen particles (22‐nm spheres and filaments) are secreted in excess compared to the 42‐nm virions. All three particles are shown at the top of the Figure. Infectious virions bind through the preS1‐domain of L‐HBs protein to a yet unknown receptor on target cells. The nucleocapsid is released into the cytoplasm and directs the partially double‐stranded DNA genome to the host nucleus where it is converted to covalently closed circular DNA (cccDNA). The cccDNA serves as a template for transcription of the pregenomic and subgenomic mRNAs that are translated in the cytoplasm. Core and polymerase (pol) proteins interact with the pregenomic RNA, and nucleocapsids are assembled from core protein dimers. The RNA is reverse transcribed, and the mature nucleocapsids either transport the relaxed circular DNA (rcDNA) back to the nucleus to form cccDNA or are exported through interaction with the preS1‐domain of L‐HBs in the endoplasmic reticulum (ER). HBcAg, HBV core antigen; L‐, M‐, S‐HBs, large, medium and small HBV surface antigens.

Figure 4.

Outcomes of HBV infection. Chronic carriers may resolve a replicative infection during an acute exacerbation, which may occur spontaneously or during IFNα therapy (dotted line).

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Further Reading

Chang JJ and Lewin SR (2007) Immunopathogenesis of hepatitis B virus infection. Immunology and Cell Biology 85(1): 16–23.

Jilbert AR, Litwin S and Mason WS (2008a) Pathogenesis of hepatitis B virus infections. In: Locarnini S and Lai CL (eds) Hepatitis B Virus Human Virus Guide, 2nd edn, Chap. 7, pp. 7.1–7.17. London: International Medical Press.

Jilbert AR, Mason WS and Kann M (2008b) Hepatitis B virus replication. In: Locarnini S and Lai CL (eds) Hepatitis B Virus Human Virus Guide, 2nd edn, chap. 4, pp. 4.1–4.13. London: International Medical Press.

Lai C‐L, Yuen M‐F and Locarnini S (2008) Treatment of chronic hepatitis B infection. In: Lai C and Locarnini S (eds) Hepatitis B Viruses, pp. 15.1–15.41. London: International Medical Press.

Lok AS (2000) Hepatitis B infection: pathogenesis and management. Journal of Hepatology 32(suppl.): 89–97.

Seeger C, Mason WS and Zoulim F (2007) Hepadnaviruses. In: Knipe DM and Howley PM (eds) Fields Virology, 5th edn, pp. 2977–3029. Philadelphia, PA: Lippincott Williams & Wilkins.

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Jilbert, Allison R, Reaiche, Georget Y, Clouston, Andrew, and Mason, William S(Jan 2011) Hepatitis B Virus. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001027.pub2]