Hepatitis B Virus (HBV)

What is Hepatitis B virus (HBV)?

Hepatitis B virus (HBV) is the pathogen that causes hepatitis B and belongs to Hepadnaviridae family, which includes two genera, orthohepatophilic DNA virus and avian hepatotropic DNA virus, and it is orthohepatotropic DNA virus that causes human infection. HBV infection is a global public health problem, and hepatitis B infection is endemic worldwide, but the epidemic intensity of hepatitis B infection varies greatly in different regions, most of which occur in children and young adults, and a small number of patients can later transform into cirrhosis or liver cancer. According to the World Health Organization, about 2 billion people worldwide have been infected with hepatitis B, of which 350 million are chronically infected with hepatitis B, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma caused by hepatitis B infection.

Hepatitis B virus genotypes

The HBV genome has a unique and precise structure, about 3.2 kb long, composed of partial double-stranded DNA (rcDNA), and the four open reading frames (ORFs) are all located in the long strands, which are S, C, P, and X, among which the S region is completely chimeric in the P region, 23% and 39% of the C and X regions overlap with the P region, and the C region and X region overlap 4~5%, and the ORF overlap makes the utilization rate of the HBV genome as high as 150%. The S zone was divided into three coding regions: pre-S1, pre-S2 and S, which encoded pre-S1 protein, pre-S2 protein (pre-S2) and HBsAg, respectively. The C region is composed of the pre-C gene and the C gene, which encode HBeAg and HBcAg. The P region encodes a variety of functional proteins, including DNA polymerase and RNase H with reverse transcription activity, which are involved in the replication of HBV. The X gene encodes the X protein, which is HBxAg.

Fig.1 The genome of Hepatitis B virus. (Carreno Vicente, et al., 2006)

Hepatitis B virus structure

The mature hepatitis B virus is spherical in shape and has a lipid envelope with a diameter of about 42 nM. The HBV genome encodes large (L), medium (M), and small (S) hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B core antigen (HBcAg), polymerase, and hepatitis B X protein (HBx). Hepatitis B virus has a bilayer capsid structure, the outer capsid is similar to the envelope of ordinary viruses, which is composed of a lipid bilayer and a protein, and HBsAg protein is embedded in the lipid bilayer. The core particle is icosahedral stereo symmetrical, and the surface of the core particle is the true capsid of the virus, which is composed of HBcAg of hepatitis B virus, and the central part is a circular and notched DNA duplex and a DNA polymerase attached to it. The length of the two strands of hepatitis B virus DNA is different, and the length of the long strand is constant and negative. The length of the short chain is variable, and it is a positive chain, and the length is about 50%~80% of the long chain (Fig.1).

Fig.2 Schematic diagram of hepatitis B virus (HBV) particles. (Herrscher Charline, et al., 2020)

Hepatitis B virus life cycle

The life cycle of HBV is as follows: First, HBV binds to the NTCP receptor and infects hepatocytes. The HBV nucleocapsid is then transported to the nucleus, and the rcDNA enters the nucleus and integrates into the human genome. The rcDNA is then converted into stable cccDNA by the host factor. cccDNA is used as a template to transcribe viral RNA. These viral RNAs are then translated into HBV proteins. At the same time, the pgRNA linked to the HBV polymerase is packaged into capsid particles. Using pgRNA as a template, the virus generates negative strands of DNA by reverse transcription, and further generates positive strands of DNA. Eventually, HBV viral particles and non-infectious subviral particles are formed and secreted.

Fig.3 Lifecycle of Hepatitis B virus. (Asselah Tarik, et al., 2019)

Hepatitis B virus spread routes

Blood-borne transmission: This is the main mode of transmission. These include unclean injections (e.g., intravenous drug users sharing syringes), acupuncture, transfusions of blood and blood products containing hepatitis virus, surgery, tooth extractions, hemodialysis, organ transplants, etc. Although you are now subjected to rigorous screening when you go to donate blood, it does not screen for HBsAg negative HBV carriers.

Mother-to-child transmission: It is mainly transmitted through the placenta, birth canal, breastfeeding and feeding. With improved sanitation technology and the combination of hepatitis B vaccine and hepatitis B immunoglobulin, mother-to-child transmission is now rare.

Sexual transmission: Unprotected sexual contact with an HBV-positive person, especially one with multiple sexual partners, is associated with a high risk of HBV infection.

Close contact transmission: Because HBsAg can be detected in the saliva, sweat, etc., close contact in life may be a special form of blood-borne transmission due to minor trauma.

Immunity to Hepatitis B virus

Hepatitis B virus (HBV) can cause abnormalities in the body's antiviral immune response through a variety of mechanisms, leading to persistent infection. Dendritic cells (DCs) are one of the full-time APCs, which can induce HBV-specific CD8⁺ T cells to eliminate viruses through cellular immune responses, and DC cells can also secrete type I interferon and proinflammatory factors to regulate immune function. The human body mainly clears hepatitis B virus through adaptive immune response, and hepatitis B virus-specific CD8⁺ T cells can directly kill hepatitis B virus-infected hepatocytes through cytotoxicity, but its main antiviral function is to secrete and produce IFNγ, TNFα, IL-2 and other cytokines, and inhibit the expression and replication of hepatitis B virus genes. Clearance of HBV infection depends on the number of HBV-specific CD8⁺ T cells with multiple secretory and killing functions.

Prevention and treatment of hepatitis B virus

Hepatitis B virus prophylaxis

Management of the source of infection: Patient registration, statistics, and guidance on disinfection, isolation and prevention for the patient's family.

Cut off the route of transmission: Pay attention to personal hygiene, keep toothbrushes, razors and other utensils from others, and do not share razors, toothbrushes and other supplies.

Protect susceptible populations: Hepatitis B vaccination is the most effective protection against HBV infection.

Hepatitis B virus treatment

Since 2010, when a significant clinical breakthrough was made in direct antiviral drugs targeting HIV and hepatitis C virus, the global research and development of chronic hepatitis B treatment drugs has begun to be active, especially anti-hepatitis B virus drugs with new mechanisms include capsid inhibitors, RNA interference drugs, Immune agonists and therapeutic vaccines have attracted the layout of many pharmaceutical companies and scientific research institutes.

Acute hepatitis: Generally, it is a self-limited disease, about 95% of patients have sufficient rest, proper nutrition, generally use liver protection drugs, vitamin supplements, and generally do not need antiviral treatment.

Chronic hepatitis: There are currently two types of anti-HBV drugs on the market, interferon alpha (conventional interferon and pegylated interferon) and five nucleoside analogues, the latter including Lamivudine, Tibivudine, Entecavir, Adefovir and Tenofovir. In addition, it can also enhance the body's non-specific immune function through immunomodulatory methods (Thymus peptide α1) with few adverse reactions.

References

• Carreno, Vicente, et al., Hepatitis B Virus and Hepatitis C Virus: Molecular Biology and Diagnosis. Perspectives in Medical Virology 13 (2006): 109-139.
• Herrscher, Charline, et al., Hepatitis B virus entry into cells. Cells 9.6 (2020): 1486.
• Asselah, Tarik, et al., Targets and future direct-acting antiviral approaches to achieve hepatitis B virus cure. The Lancet Gastroenterology & Hepatology 4.11 (2019): 883-892.

※ Please kindly note that our services are for research use only.