HBV Lifecycle


Figure 1. HBV Life Cycle.

Hepatitis B Virus (HBV) is a DNA virus that only infects and replicates in human liver cells (hepatocytes). After entry into the liver cell (inset 1), the viral capsid delivers the viral genome (relaxed circular DNA, rcDNA) to the nucleus where it is converted by host enzymes into cccDNA, an episomal replicative intermediate that can function as a mini-chromosome (inset 2). The cccDNA mini-chromosome then serves as template for the production and replication of new viral components. The HBV Core protein accumulates in the cytoplasm where it mediates capsid assembly, a self-oligomerization process in which multiple copies of the Core protein come together to form a shell containing one copy of the virus pre-genomic RNA (pgRNA) and one copy of the viral polymerase enzyme. Inside the capsid the viral polymerase enzyme converts the pgRNA to rcDNA (a step that prescribed HBV nucleoside analog drugs, such as Entecavir and Tenofovir, function to suppress but not eliminate the virus). Capsid assemblies containing rcDNA can then acquire an envelope and be secreted as new infectious viral particles (red spheres; inset 3a) or return to the hepatocyte nucleus to replenish Core and cccDNA, thus ensuring continued infection. Non-infectious sub-viral particles are secreted from the hepatocyte (inset 3b) with a coating of host-derived membrane and several copies of the HBV surface antigen protein (HBsAg, green cone structures).

Mechanism of HBV Persistence

Viral infections may be acute or chronic. Acute HBV infection results when replication of the virus kills the host cell (cytolytic infections) or when the host cell detects the virus and mounts an effective anti-viral immune response to eliminate further viral replication. Chronic HBV (CHB) infection occurs when replication within hepatocytes is not cytolytic and the virus evades the host’s innate and adaptive immune responses. Recent evidence indicates that the HBV Core protein (HBc) plays a central role in suppressing the host innate immune response. It has also been postulated that HBsAg may contribute to the suppression of the adaptive or cellular immune response, thus hampering elimination of infected cells.