Molecular biology of the hepatitis B virus and role of the X gene

Abstract

The hepatitis B virus (HBV) is a widespread human pathogen and a major health problem in many countries. Molecular cloning and sequencing of the viral DNA genome has demonstrated a small and compact structure organized into four overlapping reading frames that encode the viral proteins. Besides structural proteins of the core and the envelope, HBV encodes a DNA polymerase with reverse transcriptase activity, a secreted antigen of unknown function, and a transcriptional activator that is essential for viral replication. Major steps of the viral life cycle have been unraveled, including transcription of all viral RNAs from nuclear covalently closed circular DNA (cccDNA), followed by encapsidation of pregenomic RNA, a more-than-genome length transcript, and reverse transcription of pregenomic RNA leading to asymmetric synthesis of the DNA strands. Although HBV has been recognized as a human tumor virus, no direct transforming activity could be evidenced in different cellular and animal models. However, the transcriptional regulatory protein HBx encoded by the X gene is endowed with weak oncogenic activity. HBx harbors pleiotropic activities and plays a major role in HBV pathogenesis and in liver carcinogenesis.

Résumé

Le virus de l’hépatite B (VHB) est un petit virus à ADN qui représente l’un des virus pathogènes les plus répandus dans le monde et constitue un sérieux problème de santé publique. Le clonage moléculaire du génome viral et la détermination de sa séquence nucléotidique ont révélé une petite structure compacte organisée en quatre phases ouvertes de lecture chevauchantes qui codent pour les protéines virales. Le génome du VHB code pour les protéines structurales constituant l’enveloppe et la capside, pour une ADN polymérase qui possède une fonction de reverse transcriptase, pour un transactivateur transcriptionnel et pour un antigène secrété de fonction mal définie. Les principales étapes du cycle viral ont été identifiées, notamment la transcription d’une forme d’ADN nucléaire, épisomale circulaire fermée (cccDNA) qui permet la synthèse de tous les ARN viraux, puis l’encapsidation de l’ARN prégénomique, un transcrit plus long que le génome, et la synthèse asymétrique des deux brins d’ADN viral par réverse-transcription de l’ARN prégénomique. Bien que le VHB soit largement reconnu comme l’un des virus tumorigènes humains, aucune activité directement transformante n’a pu être mise en évidence dans différents modèles cellulaires et animaux. Cependant, la protéine transactivatrice HBx codée par le gène X est dotée d’une faible activité oncogénique, et cette protéine multifonctionnelle joue un rôle clé dans la réplication virale et dans le processus tumoral associé à l’hépatite B chronique.

Introduction

Acute and chronic hepatitis B are major liver diseases in the world and presently, around 350 million chronic carriers worldwide face a drastically increased risk of developing liver cirrhosis and hepatocellular carcinoma [1], [2]. Although hepatitis B affects all countries in the world, its geographical distribution is highly variable, with chronic carrier rates ranging from more than 10% in endemic regions (mainly South-East Asia and Sub-Saharan Africa) to less than 0.5% in non-endemic regions such as Northern Europe and Northern America. Moreover, important variations have been noted among different ethnic groups in the same country. Such heterogeneity that reflects different routes of transmission has allowed to unveil a tight epidemiological association between chronic hepatitis B and hepatocellular carcinoma [3].

The viral origin of hepatitis B was first recognized by the early studies that identified the “Australia” antigen as a viral surface antigen (HBsAg) in the serum of chronic hepatitis patients [4], [5]. The hepatitis B virus (HBV) DNA genome was shown to represent the smallest known animal virus genome [6]. Molecular cloning of the HBV genome and nucleotide sequencing have represented a major breakthrough for subsequent studies of hepatitis B pathogenesis [7], [8], [9], [10]. In particular, HBV has been identified as the first DNA virus encoding a reverse transcriptase [11], and the structure and function of the different viral proteins and the replicative cycle of HBV have been extensively characterized [12]. Moreover, the recombinant DNA technology could be efficiently applied to the production of empty envelope particles endowed with high antigenicity [13], successfully used for vaccination against hepatitis B. The hepatitis B vaccine, which prevents chronic HBV infection and related liver diseases, has been introduced into national immunization programs for children in 89% of countries, including poverty-stricken countries [14]. The efficacy of this vaccine in lowering the rate of chronic HBV carriers as well as the incidence of liver cancer has been fully demonstrated in Taiwan, a highly endemic region [15].