Hepatitis B virology for clinicians

Abstract

A basic understanding of the molecular events involved in the hepatitis B virus (HBV) life cycle is essential to better appreciate the natural history and atypical presentations of the disease and to develop individual management plans based on readily available virologic tests. With the improved knowledge gained from studying the molecular biology of HBV, novel approaches to inhibition of viral replication are being explored, such as viral entry inhibitors, nucleocapsid inhibitors, and inhibitors of viral assembly. However, the ultimate goal of therapy is to identify strategies to eliminate covalently closed circular DNA from infected hepatocytes. This article serves to introduce the clinically relevant aspects of the HBV life cycle as they pertain to patient management.

Fig. 1.

The viral genome is represented by the inner, black circles. It is a relaxed circular partially double-stranded DNA. The DNA’s circularity is maintained by 5°-cohesive ends containing 2 11-nucleotide direct repeats that are important for viral replication. The 2 strands are asymmetric. The minus strand is genome length and is covalently linked at its 5°end to the terminal protein domain of polymerase. The positive strand is of variable length and has a capped oligoribonucleotide on its 5° end. The genome has 4 open reading frames, which overlap due to the compact nature of the genome. These are all encoded by the minus strand and consist of the polymerase, precore/core, pre-S1/pre-S2, s/pre-s, and X. Finally, the outer wavy lines represent 4 viral messenger RNA (mRNA) species. The 3.5-kb pregenomic mRNA is genome length and the other 3 are subgenomic length. All terminate in a poly A tail.

Fig. 2.

Comparison of change in cccDNA, intrahepatic, and serum HBV-DNA levels after anti- viral therapy for 48 to 52 weeks.

Fig. 3.

The small compact genome and the requirement of host cellular enzymes for many stages of the HBV life cycle have been an impediment to antiviral drug development. However, a better understanding of the HBV life cycle has identified several molecular targets and compounds that can disrupt new virion formation. These include viral entry inhibitors, encapsidation inhibitors, and agents that prevent viral assembly and coating. Heteroaryldihydropyrimidines (HAPs) bind to the core particles and lead to their degrada- tion. Another group of compounds that inhibit the encapsidation step are phenylpropena- mides. These compounds directly inhibit formation of the nucleocapsid. Antisense RNA and short interfering RNA (siRNA) have been shown to inhibit viral assembly in vitro and in animal models. Glucosidase inhibitors block the glycosylation of surface proteins during the viral assembly step. Recently, pre-S1 derived lipopeptides were shown to be potent inhibitors of HBV entry and may be useful after liver transplantation and perhaps in chronic hepatitis B. (From Ghany M, Liang TJ. Drug targets and molecular mechanisms of drug resis- tance in chronic hepatitis B. Gastroenterology 2007;132:1574–85; with permission.)