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Chapter 31 : Hepatitis B Virus

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Abstract:

The goal of chemoprevention for chronic hepatitis B (CHB) must be to improve the quality and the outcomes of care for patients with CHB. This chapter focuses on the human hepatitis B virus (HBV). HBV is an enveloped, 3.2-kb double-stranded DNA virus which may be classified into eight major genotypes (A to H) based on a nucleotide diversity of 8% or more. HBV infection is usually diagnosed using specific serologic assays. During the course of infection, the viral proteins HBsAg, HBcAg, and HBeAg stimulate the immune system to produce the corresponding antibodies anti-HBs, anti-HBc, and anti-HBe. Once HBV DNA becomes detectable, replication increases exponentially to peak at levels of >10 copies/ml in serum. In adult-acquired acute HBV infection, in which the host is able to control the virus, viral replication then declines, preceding the onset of clinical hepatitis. The risk of fulminant hepatic failure (FHF) may be higher in patients acutely infected with basal core promoter (BCP) or precore variants, coinfected with other hepatitis viruses, or with underlying liver disease. The major complications of CHB are cirrhosis, hepatic decompensation, and HCC. The current challenge in CHB is to identify patients at risk for progressive liver disease, so that therapy may be offered early to alter the natural history. The major risk factors for progression to cirrhosis are viral load, the presence of fibrosis on liver biopsy, and elevated serum alanine aminotransferase (ALT).

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31

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Image of FIGURE 1
FIGURE 1

(A) Electron micrograph of the various forms found in the blood of HBV-infected persons. The 42-nm virions, both full and empty, can be seen. Within the empty particles, the 27- to 32-nm core structure can be visualized. The excess 22-nm subviral particles and filamentous forms of HBsAg are also present. (B) The circular double-stranded DNA genome of HBV showing the four main ORFs. The minus (–) and plus (+) DNA strands are marked. The HBV Pol and capped mRNA oligomer at the 5′ end of the minus and plus strands, respectively, as well as DR1 and DR2 are shown. The space between DR1 and DR2 is the “cohesive overlap region.” The plus strand is typically incomplete.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 2
FIGURE 2

(A) Biosynthesis of the precore/core, Pol, envelope, and X proteins from the various HBV transcripts. The two major genomic 3.5-kb transcripts are the larger precore mRNA from which the precore protein (HBeAg) is made and the smaller pgmRNA that encodes the core and Pol and is the template for reverse transcription. The single 2.4-kb RNA makes LHBs, while the various 2.1-kb mRNAs translate MHBs and SHBs. The HBx protein is translated from the 0.7-kb mRNA. (B) Functional domains of the Pol-reverse transcriptase of HBV. (C) HBV DNA genome showing the overlapping ORFs and, in particular, how the Pol-envelope overlap can affect each of the proteins during the emergence of NA drug resistance.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 3
FIGURE 3

Replication cycle of HBV. Following attachment, penetration, and uncoating, the viral nucleocapsid is released into the cytosol and transported to the nuclear pore. The genomic DNA is delivered into the nucleus, where it is converted into cccDNA and the viral minichromosome is generated. Transcription of the viral minichromosome produces the genomic and subgenomic HBV mRNA transcripts. Translation of the pgRNA in the cytosol produces the core and Pol proteins, and in association with HSP60 all are selectively packaged into a replication complex. Within the nucleocapsid, reverse transcription begins. The envelope proteins (pre-S1, pre-S2, and S) are translated at the rough ER and then bud into the lumen of the intermediate compartment. Approximately 50% of the pre-S1-enriched ER membrane areas envelope core particles. The HBV virions, small particles, and tubules are then secreted into the extracellular space by the constitutive pathway. The nucleocapsids can also be transported to the nucleus via an intracellular conversion pathway, increasing the copy number of cccDNA molecules.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 4
FIGURE 4

Diagrammatic representation of the epsilon (ε) stem-loop structure of HBV. This is a highly conserved structure within the eight genotypes of HBV. The positions of base changes for genotype A-2 (Ae) are shown, as are the common translational precore mutations of G1896A (precore stop codon: UAG) and G1899A.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 5
FIGURE 5

Location of the primary mutations associated with LMV and LdT resistance as well as ADV, TDF, and ETV resistance, in the major catalytic domains of the HBV Pol gene. a.a., amino acids.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 6
FIGURE 6

Natural history of CHB, showing relationships between serology, biochemistry, molecular virology (serum and liver compartment), and immunologic parameters of the innate and adaptive arms. (Adapted from reference .)

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 7
FIGURE 7

The host immune response directed against HBV requires coordinated action of both innate immunity and cellular and humoral adaptive immunity, to affect both noncytolytic and cytolytic activity. The pathways of noncytolytic clearance are highlighted (see text). The key cytokines involved are IFN-γ, TNF-α, and IFN-α/β. IFN-γ and TNF-α, secreted by antigen-specific CTL or by the antigen-nonspecific macrophages and T cells that they activate, abolish HBV gene expression and replication in the livers of transgenic mice without killing the hepatocytes. These cytokines activate two independent virocidal pathways. The first pathway eliminates HBV nucleocapsid particles and their cargo of replicating viral genomes, by preventing capsid assembly in a proteasome- and kinase-dependent manner. The second pathway destabilizes the viral RNA by an SSB/La-dependent mechanism. IFN-γ and TNF-α induce proteolytic cleavage of the La autoantigen, which normally protects several HBV RNA endoribonuclease cleavage sites from cellular RNases. Type I IFN (IFN-α/β) also inhibits HBV replication at a posttranscriptional level. IFN-β has been shown to activate hepatocellular mechanisms that prevent the formation of replication-competent HBV capsids. The molecular mechanism(s) that mediates this inhibition has not yet been defined; type I IFN-inducible genes with known antiviral activity, including those for double-stranded RNA-dependent protein kinase and interferon regulatory factor 1, have been implicated. Type I IFNs have also been shown to inhibit transcription of HBV RNAs in some models.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 8
FIGURE 8

Global prevalence of HBsAg. The WHO clarifies areas as being of high, medium, or low endemicity for HBV if the prevalence rate of HBsAg is >8, 2 to 7, or <2%, respectively.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 9
FIGURE 9

HBV DNA level predicts the risk of cirrhosis (light gray bars) and HCC (dark gray bars). Elevated serum HBV DNA level (>10 copies/ml) is a strong predictor of risk for both cirrhosis and HCC. (Adapted from references and .)

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Image of FIGURE 10
FIGURE 10

Impact of universal vaccination on the incidence of HCC in Taiwan. A universal vaccination program was implemented in Taiwan in July 1984. Subsequently, the incidence of HCC was found to decline ( < 0.01 for the comparison of values before July 1990 with those after July 1990). (Adapted from reference .)

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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Tables

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TABLE 1

Taxonomy of

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
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TABLE 2

Overview of the eight genotypes of HBV

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Generic image for table
TABLE 3

Profile of serologic markers for HBV infection