Hepatitis B virus molecular biology and pathogenesis

Abstract

As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350-500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, we provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and we highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

Keywords: Hepatitis B virus; hepatitis B virus life cycle; hepatitis B virus-associated disease; hepatocellular carcinoma.

Figure 1

Molecular biology of hepatitis B virus (HBV). (A) Scaled depiction of the HBV (genotype ayw) genome. Internal circle shows genomic position relative to EcoRI site. Partially double-stranded genome is depicted with attached RNA primer and polymerase protein. Open reading frames (ORFs) are indicated by the thicker, colored lines. The outermost black circles represent the viral transcripts with the shared polyadenylation site. (B) Schematic representation of the overlapping nature of the HBV ORFs. C. The mature HBV virion (Dane particle) consists of two main parts: a nucleocapsid (or core particle) consisting of a partially double-stranded DNA genome bound to polymerase (P) and encapsidated by dimers of core protein, and a viral envelope consisting primarily of S-HBsAg (S), with an intermediate amount of M-HBsAg (M) and lower levels of L-HBsAg (L).

Figure 2

Life cycle of hepatitis B virus (HBV). Mature HBV virions enter hepatocytes through the sodium taurocholate cotransporting polypeptide receptor on the cell membrane. After release from the viral envelope, the nucleocapsid is then transported to the nucleus where the genome is repaired to form covalently-closed circular DNA (cccDNA). Using cccDNA as the template, viral RNAs are transcribed and exported into the cytoplasm where they are translated to form the viral proteins. Additionally, pregenomic RNA (pgRNA) is packaged by core protein, along with the polymerase protein, and the viral genome is replicated through reverse transcription of the pgRNA to form the - strand, followed by partial synthesis of the + strand. Mature nucleocapsids can then either be recycled back to the nucleus to maintain a pool of cccDNA, or enveloped and secreted through the ESCRT pathway. See text for a more detailed description of viral life cycle.

Figure 3

The natural history of an hepatitis B virus (HBV) infection. Infection with HBV typically results in an acute, self-clearing infection. Alternatively, infected individuals could develop a chronic infection, which typically follows a long-term course in which the virus replicates at high levels, followed by immune-mediated control of viral replication associated with liver inflammation. Seroconversion and maintenance of undetectable or low levels of viral replication are markers of a favorable prognosis, but long-term disease can lead to the development of cirrhosis and hepatocellular carcinoma.