Chapter 32 : Hepatitis B Virus

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It has been over 40 years since the discovery of the hepatitis B virus (HBV), and yet the disease it causes remains a major public health challenge. Worldwide, over 240 million people have chronic hepatitis B (CHB), with the majority being in the Asia-Pacific region, and there are almost 800,000 deaths each year as a direct consequence of infection (2). HBV infection is the ninth leading cause of death worldwide. The main public health strategy to control hepatitis B infection for the last 30 years has been primary prevention through vaccination. According to WHO, as of 2013, more than 180 countries have now adopted a national policy of immunizing all infants with hepatitis B vaccine. However, a strategy of secondary prevention is clearly necessary to reduce the risk of long-term complications (cirrhosis, liver failure, and hepatocellular carcinoma) in those individuals who have CHB. The risk of these complications is strongly associated with persistent high-level HBV replication (3–5). Antiviral agents active against HBV are available. The long-term suppression of HBV replication has been shown to prevent progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC) and liver-related deaths. However, currently available treatments fail to eradicate the virus in most of those treated, necessitating potentially lifelong treatment. WHO has set targets for both morbidity and mortality. A cure for CHB remains elusive, and a significant research effort is now being directed toward this goal.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 1A

Electron micrography 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.

The circular double-stranded DNA genome of HBV showing the four main open reading frames (ORFs). The minus (-) and plus (+) DNA strands are marked. The HBV Pol and capped mRNA oligomer at the 5′ end of the (-) and (+) strands, respectively, as well as DR-1 and DR-2 are shown. The space between DR-1 and DR-2 is the “cohesive overlap region.” The plus strand is typically incomplete.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 2A

Biosynthesis of the precore/core, polymerase, 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 pregenomic mRNA that encodes the core and polymerase 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.

The functional domains of the polymerase-reverse transcriptase of HBV See Bartholomeusz et al. ( ) for a more detailed discussion.

Linear, schematic representation of the core protein amino acid residues and the immunodominant B cell and T cell epitopes. See text for details.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 3

Diagrammatic representation of the epsilon (ε) stem-loop structure of HBV. This is a highly conserved structure within the 10 genotypes of HBV, and the positions of base changes for genotype A2 are shown, as are the common translational precore mutations at G1896A (precore stop codon: UAG) and G1899A.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 4

Life cycle of HBV. Following attachment, penetration, and uncoating, the viral nucleocapsid is released into the cytosol and transported to the nuclear pore. The relaxed circular 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 pregenomic RNA in the cytosol produces the Core and Pol proteins, and, in association with Hsp-60, all are selectively packaged into a replication complex. Within the nucleocapsid, reverse transcription begins. Synthesis of the (+) DNA strand proceeds from the RNA primer to the 5′ end of the (-) DNA strand ( ). The short terminal redundancy of the (-) DNA strand permits the transfer of the 3′ end of the growing short (+) strand from the protein-linked 5′ end to the 3′ end of the minus strand, thereby circularizing the genome and allowing continuation of DNA synthesis, generating the genomic RC DNA molecule with the HBV Pol covalently attached to the 5′ end of the (-) DNA strand. The envelope proteins Pre-S1, Pre-S2, and S are translated at the rough endoplasmic reticulum (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 and subviral particles are then secreted into the extracellular space by usurping the cellular ESCRT pathway. The nucleocapsids can also be transported to the nucleus via an intracellular conversion pathway, thereby increasing the number of nuclear cccDNA molecules.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 5

Global prevalence of HBsAg, WHO clarifies areas of high, medium, or low endemicity for HBV if the prevalence rates of HBsAg are ≥8%, 2 to 7%, or <2% respectively. (Adapted with permission from Ott et al. [ ]).

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 6

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 section “Pathogenesis”).

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 7

The natural history of chronic hepatitis B, showing relationships between serology, biochemistry, molecular virology (serum and liver compartment), as well as immunological parameters of the innate and adaptive arms.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 8

Nomograms for the predicted risk of (A) liver cirrhosis (low risk <11; moderate risk 11 to 16; high risk ≥17), and (B) HCC (low risk <9; moderate risk 9 to 12; high risk ≥13). These have been developed using identified virologic and host factors that increase risk of complications. The scoring system is outlined in Table 2 . Reproduced with permission from Lee et al. ( ).

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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Image of FIGURE 9

HBV DNA genome showing the overlapping open reading frames (ORFs) of POL and S, and, in particular, how the polymerase-envelope overlap can affect each other during the emergence of NA resistance.

Citation: Wong D, Locarnini S, Thompson A. 2017. Hepatitis B Virus, p 713-770. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch32
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