HBV Replication Cycle
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HBV Replication Cycle
HBV (Hepatitis-B Virus) belongs to a family of closely related DNA viruses called the Hepadnaviruses. Included in this family are the WHV (Woodchuck Hepatitis Virus), the DHBV (Duck Hepatitis-B Virus) and several other avian and mammalian variants. Hepadnaviruses have a strong preference for infecting liver cells, but small amounts of hepadnaviral DNA can be found in kidney, pancreas, and mononuclear cells. However, infection at these sites is not linked to extra hepatic disease (Ref.1). The HBV nucleocapsid contains a relatively small and partially duplex 3.2 Kb circular DNA, viral polymerase and core protein. The genome has only four long open reading frames. The preS-S (presurface-surface) region of the genome encodes the three viral surface antigens by differential initiation of translation at each of three in-frame initiation codons. The most abundant protein is the 24-KD S protein (which is known as HBsAg). The preC-C (precore-core) region encodes HBcAg (Hepatitis-B core Antigen) and HBeAg (Hepatitis-B e Antigen). HBeAg is not required for viral replication and plays no role in viral assembly. The P-coding region is specific for the viral polymerase, a multifunctional enzyme involved in DNA synthesis and RNA encapsidation. The X open reading frame encodes the viral X protein (HBx), which modulates host-cell signal transduction and can directly and indirectly affect host and viral gene expression (Ref.2).

The life cycle of HBV is believed to begin when the virus attaches to the host cell membrane via its envelope proteins. It has been suggested that HBV binds to a receptor on the plasma membrane that is predominantly expressed on human hepatocytes via the pre-S1 domain of the large envelope protein as an initial step in HBV infection. However, the nature of the receptor remains controversial. Then, the viral membrane fuses with the cell membrane and the viral genome is released into the cells. The replication of HBV can be regulated by a variety of factors, including hormones, growth factors, and cytokines. After the viral genome reaches the nucleus, the viral polymerase converts the partial dsDNA (double stranded DNA) genome into cccDNA (covalently closed circular DNA). This DNA is transcribed by host RNA Pol-II, and the resulting DNA is the template for further propagation of pre-genomic RNA and sub-genomic RNA (Ref.4). The pre-genomic RNA is bifunctional serving as both the templates for viral DNA synthesis and as the messenger for pre-C, C, and P translation. The subgenomic RNAs function exclusively for translation of the envelope and X protein. All viral RNA is transported to the cytoplasm, where its translation yields the viral envelope, core, and polymerase proteins, as well as HBx and HBcAg. HBV core particles are assembled in the cytosol and during this process a single molecule of pre-genomic RNA is incorporated into the assembling viral core. Once the viral RNA is encapsidated, reverse transcription begins. The synthesis of the two viral DNA strands is sequential. The first DNA strand is made from the encapsidated RNA template; during or after the synthesis of this strand, the RNA template is degraded and the synthesis of the second DNA strand proceeds, with the use of the newly made first DNA strand as a template. Some cores bearing the mature genome are transported back to the nucleus, where their newly minted DNA genomes can be converted to cccDNA to maintain a stable intranuclear pool of transcriptional templates (25-Ref.5). HBV surface (HBsAg) proteins are initially synthesized and polymerized in the rough endoplasmic reticulum. These proteins are transported to the post ER and pre-Golgi compartments where budding of the nucleocapsid follows. The assembled HBV virion and sub-viral particles are transported to the Golgi for further modification of its glycans in the surface proteins, and then are secreted out of the host cell to finish the life cycle.

HBV infection is highly species specific; only humans and closely related species are known to be susceptible to HBV infection. It is transmitted by percutaneous and mucous membrane exposure to infected blood and to infected body fluids that contain blood. In most Western countries, the major routes of transmission among adults are illicit injection, drug use and sexual contact. Almost all adults newly infected with HBV develop acute hepatitis with jaundice as a predominant feature (Ref.3). Infection with HBV results in a broad spectrum of liver disease, ranging from subclinical infection to acute, self-limited hepatitis and fatal, fulminant hepatitis. Exposure to HBV, particularly when it occurs early in life, may also result in an asymptomatic carrier state that can progress to chronic active hepatitis, cirrhosis of the liver, and eventually hepatocellular carcinoma. Persistent infection with HBV represents a major health problem worldwide, with more than 350 million chronically infected patients at risk of developing liver disease. Many chronically infected individuals eventually acquire severe liver disease that may progress to hepatocellular carcinoma, one of the most common forms of human cancer. The association between HBV infection and the development of liver cancer has stimulated interest in the production of therapeutic strategies for both the prevention of HBV infection and the clearance of virus from those who are chronically infected. While the implementation of HBV vaccine programs has decreased the number of new chronic infections in some parts of the world, it has no impact on those already infected. HBV therefore continues to be a pathogen of major importance. The present therapies for individuals chronically infected with HBV include treatment with Alpha interferon, Lamivudine (3TC), or Adefovir Diprovoxil (Ref.6).