Overview of hepatitis B viral replication and genetic variability

Abstract

Chronic infection with hepatitis B virus (HBV) greatly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). HBV isolates worldwide can be divided into ten genotypes. Moreover, the immune clearance phase selects for mutations in different parts of the viral genome. The outcome of HBV infection is shaped by the complex interplay of the mode of transmission, host genetic factors, viral genotype and adaptive mutations, as well as environmental factors. Core promoter mutations and mutations abolishing hepatitis B e antigen (HBeAg) expression have been implicated in acute liver failure, while genotypes B, C, subgenotype A1, core promoter mutations, preS deletions, C-terminal truncation of envelope proteins, and spliced pregenomic RNA are associated with HCC development. Our efforts to treat and prevent HBV infection are hampered by the emergence of drug resistant mutants and vaccine escape mutants. This paper provides an overview of the HBV life cycle, followed by review of HBV genotypes and mutants in terms of their biological properties and clinical significance.

Keywords: HBV; Replication; Variability.

Fig. 1

HBV life cycle. HBV enters hepatocytes through NTCP, followed by uncoating, and nuclear transport of the RC DNA. The RC DNA is converted to cccDNA, which serves as the template for transcription of the 3.5 kb preC RNA and pgRNA, 2.4- and 2.1-kb preS/S mRNAs, and 0.7-kb HBx mRNA. These RNAs are exported to cytoplasm for protein translation. pgRNA is selectively packaged inside core particles, followed by P protein-mediated (−) strand DNA synthesis (reverse transcription), pgRNA degradation, and (+) strand DNA synthesis to generate RC DNA. Such mature core particles can be enveloped for release as virions, or transported to the nucleus to generate more cccDNA. Double stranded linear DNA is an aberrant replication product of pgRNA, and the preferred template for integration into host chromosomal DNA.

Fig. 2

Genetic organization of the HBV genome and mechanisms of viral protein translation. Shown innermost is the P (polymerase) ORF overlapping completely with the preS1/preS2/S ORF, and partially with preC/C ORF and X ORF. Next are partially double stranded DNA genome found inside virions, with the (−) strand DNA having the P protein attached to its 5’ end and the (+) strand DNA having incomplete 3’ end (dashed line). The two direct repeat (DR) sequences, DR1 and DR2, are critical for HBV DNA replication and genome circularization. The outmost are four classes of HBV RNAs transcribed from the cccDNA template: 0.7-kb X mRNA (for HBx protein), 2.1-kb S mRNA (for M and S proteins), 2.4-kb preS mRNA (for L protein), and 3.5-kb pgRNA (for core and P proteins). In addition, the 3.5-kb precore RNA (not shown) is used for HBeAg expression.

Fig. 3

Domain structure of the P protein and mutations in its RT domain conferring resistance to NAs. The RT domain can be subdivided into seven subdomains, and mutations conferring resistance to LMV, L-dT, ADV/TFV, and ETV are shown. Adapted from Zoulim and Locarnini [155].