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Chapter 8 : Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma

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Abstract:

One factor that has been of great importance to the study of hepatitis B virus (HBV) replication, and which will become of increasing importance in characterizing the biology of infection, is the existence of hepadnaviruses in other species. The two families of viruses infecting mammals and birds are subdivided into and , respectively. To appreciate the hepadnavirus replication scheme, it is important, first, to appreciate that hepadnaviruses have one of the smallest of all animal virus genomes. The viral envelope proteins are produced in greater abundance than required for virion production. Traditionally, the envelope gene and the corresponding regions of the envelope proteins are divided into preSl, preS2, and S domains. The hepadnaviruses all replicate via reverse transcription. However, despite some similarities to retrovirus replication, an important difference is that hepadnavirus replication does not involve formation of an integrated provirus. The potentially important but poorly understood issue in the biology of infections is the effect of hepatocyte proliferation on virus replication and on the evolution of liver disease. Constant stimulation of progenitor cell proliferation may be important in the disease process leading to hepatocellular carcinoma (HCC), tumors possibly arising from incompletely differentiated progenitor cells. The International Agency for Research on Cancer evaluated the evidence and concluded that "chronic infection with HBV is carcinogenic to humans" and classified HBV as a group 1 carcinogen. Therapy with a nucleoside analog inhibitor of virus replication appears likely, from preliminary results, to have the same limitation as interferon (IFN).

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8

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Figures

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Figure 1

The HBV genome. The placement of the various open reading frames and of the viral mRNAs relative to the relaxed circular virion DNA is shown. The RNAs are represented by solid lines on the outside of the diagram, and the coding regions are represented by lines with arrowheads. The short solid arrows indicate the start sites of the various viral RNAs. All end at a common polyadenylation site within the core gene.

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8
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Image of Figure 2
Figure 2

Hepadnavirus replication. The pathway for viral DNA synthesis is shown (see text and reference 116 for details). Virus, shown at the top left (A), may contain either circular or linear, partially double-stranded DNA. Following infection, viral DNA is delivered to the nucleus, where the DNA is completed and converted to a CCC form (B). The CCC DNA acts as the template for transcription of viral mRNAs, including a large terminally redundant RNA known as the pregenome (see Fig. 1). The pregenome has the capacity to act as mRNA for both the viral nucleocapsid (core protein) and the viral RT. Translation of the RT is infrequent, but when it occurs, this protein binds a stem-loop region at the 5′ end of the RNA known as epsilon (C) ( ). The complex is then assembled into viral nucleocapsids, where reverse transcription actually takes place. Initiation of minus-strand synthesis begins at a bulge in the stem-loop structure, from which four bases are copied, using a tyrosine-OH located in the N-terminal region of the RT as a primer ( ). The complex then translocates and base pairs to a homologous four-base sequence in the 3′-terminal redundancy of the pregenome, at a 10-to-12-base sequence known as DR1 (DR1 was so named because there is a copy of this sequence outside the terminal redundancy, about 50 to 200 bases upstream in different hepadnaviruses, denoted DR2). Reverse transcription then extends to the 5′ end of the minus strand as the pregenome is degraded by the viral RNase H. The capped 5′ end of the pregenome, 17 to 18 bases in length and extending through DR1, is retained and serves as the primer of second (plus)-strand synthesis ( ). Normally, priming occurs after a translocation event in which the primer is dissociated from DR1 and annealed to DR2 (D). The mechanism of translocation is unknown. Occasionally, stable translocation fails to occur and priming occurs at DR1 to produce linear viral genomes (E) ( ). Following extension to the 5′ end of the minus strand, plus-strand synthesis jumps to the 3′ end to create a circular DNA molecule. Circularization is apparently facilitated by the short (8 to 9 bases) terminal redundancy on the minus strand ( ). Plus-strand synthesis is never completed during virus assembly, and most virion DNA has a partially double-stranded, relaxed circular conformation, though some is linear. The RT, which served as the primer of reverse transcription, and the RNA, which primed plus-strand synthesis, remain attached to the DNA strands in mature virus.

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8
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Image of Figure 3
Figure 3

Prevalence of serum HBV DNA in HBV carriers from two different populations by age group. The presence of HBV DNA (virions) in serum was determined by standard filter DNA hybridization assays. The percent of carriers scoring positive in each age group, from 20 to 60 years, is shown. Further details are provided in the text.

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8
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