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Chapter 37 : Molecular Detection and Characterization of Hepatitis B Virus

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Abstract:

Hepatitis B virus (HBV) is a small, enveloped DNA virus belonging to the family that causes transient or persistent (chronic) infection of the liver. The appreciation of clinical syndromes of acute and chronic hepatitis laid the foundation for the discovery of each of the human hepatitis viruses. Generation of multiple surface proteins from a single reading frame occurs by translation initiation at separate AUG codons within a transcript rather than by generation and cleavage of precursor proteins (as occurs with hepatitis C virus [HCV]). The focus of molecular testing is instead the characterization, treatment, and management of chronic hepatitis B (CHB) infection. Compared to antibody-based detection methods for other viruses, serologic detection of HBV is relatively sensitive due to overexpression of surface antigen (HBsAg) as noninfectious subviral particles. Nucleic acid testings (NATs) for intrahepatic HBV replication intermediates such as covalently closed circular DNA (cccDNA) have been used to characterize viral replication and evaluate antiviral therapies but are not available for routine clinical use. The earliest examples of commercial HBV NATs were quantitative, reflecting the clinical utility of HBV DNA as a surrogate for measurement of infectious hepatitis B virion burden. Given the extreme genetic variability of the HBV genome, attention will hopefully be focused on development of improved chemistries for accommodation of polymorphisms in viral load assays to reduce the risk of under quantification.

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37

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Partially Double-Stranded Circular DNA
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Figures

Image of FIGURE 1
FIGURE 1

Organization of the HBV genome. The inner circles depict the plus and minus strands of the partially double-stranded DNA genome. The overlapping ORFs C, P, S, and X encoded by the genome are represented by the bold arrows. Outer circles indicate the lengths in kilobases of pregenomic and transcribed mRNAs. The approximate location of the YMDD motif of the reverse transcriptase domain is also indicated.

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37
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Image of FIGURE 2
FIGURE 2

Replication cycle of HBV. Following entry of the virion into the host hepatocyte via receptor-mediated endocytosis and shedding of the envelope, viral DNA is translocated to the nucleus where it is processed to cccDNA, which serves as a template for the transcription of pregenomic and subgenomic mRNAs. These mRNAs exit the nucleus and are translated to produce viral proteins. The RNA pregenome is used as a template by HBV polymerase for positive-strand DNA synthesis. Newly synthesized positive strands of DNA are either packaged into complete virions or are trafficked back to the nucleus to serve as templates.

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37
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Image of FIGURE 3
FIGURE 3

Chemical structures of the approved NRTIs grouped by drug class.

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37
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Image of FIGURE 4
FIGURE 4

Mutations associated with antiviral drug resistance and their locations relative to the conserved regions of the HBV polymerase reverse transcriptase (rt) domain. LAM, lamivudine; ADV, adefovir; ETV, entecavir; LdT, telbivudine; TDF, tenofovir.

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37
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Image of FIGURE 5
FIGURE 5

The three most common mutations associated with reducing or preventing HBeAg production. The mutations A1762T and G1764A are located in the basal core promoter (BCP) region, which lies within the X gene ORF. The G1896A mutation is found in the precore (PC) region and results in the premature termination of the precore/core protein at codon 28 (TGG→TAG).

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37
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Tables

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TABLE 1

Available viral load assays

Citation: Hillyard D. 2011. Molecular Detection and Characterization of Hepatitis B Virus, p 579-592. In Persing D, Tenover F, Tang Y, Nolte F, Hayden R, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555816834.ch37

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