Virological Factors Involved in AECHB

Abstract

This chapter describes the features of HBV replication in AECHB, correlation of HBV genotypes, recombination, quasispecies, mutations, viral proteins, gene regulation post gene transcription and viral replication and their contribution to AECHB and HBV ACLF. 1. HBV belongs to the hepadnaviridae family. The HBV virion genome consists of an incomplete annular double-stranded DNA molecule approximately 3.2 kb in size. HBV has four overlapping open reading frames (ORFs), which encode the S, C, X and Polymerase (P) genes. 2. Upon entry into the nucleus of host cells, HBV DNA forms a covalently closed circular form called cccDNA. The (−) strand of cccDNA is the template for transcription of mRNAs of different length. The 3.5 kb mRNA is called pregenome; shorter, subgenomic transcripts are translated into virus proteins. cccDNA is stable in the nucleus and all current antiviral drugs that inhibit viral polymerase are unable to clear the cccDNA, explaining why chronic hepatitis B rebounds frequently. 3. The receptor-binding region of pre-S1 has been reported to interact specifically with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver and shown to be a functional receptor for HBV. 4. Diversification of HBV strains has produced eight genotypes, A–H, which differ in more than 8% of the complete genome, as well as different subgenotypes, which differ by 4–8%. HBV polymerase lacks proofreading function, thus misincorporation of nucleotide mutations occurs during viral replication. HBV genotype B and the G1896A mutation in the preC gene may be associated with the development of acute-on-chronic liver failure. 5. HBx can activate many host genes, including those encoding hfgl2, IL-2, MIG and IP-10, all of which are inflammatory and chemotactic factors involved in the progression of AECHB. The HBc- and HBs-related YMDD mutation can activate the hfgl2 gene, a mechanism resulting in AECHB. 6. HBV transcription is regulated by many transcription factors, including liver-enriched transcription factors, other normal transcription factors (e.g. HNF4, PPARα, HNF3 and HNF1) and HBx protein. Changes in host transcriptional factors may lead to changes in HBV replication, which may result in AECHB.