THE THREAT FROM HEPATITIS B
REASONS WHY IT IS FATAL AND NEW WAYS TO ERADICATE IT
Yucheng Xiang, Yicong Ma, Shuting Huang, Cheng Peng
1. Introduction
• Hepatitis B is the most common
serious liver infection in the world (1).
• It is a viral infection caused by the
hepatitis B virus which can be
transmitted through blood and infected
bodily fluids (2).
• An estimated 257 million people are
living with hepatitis B virus infection
(defined as hepatitis B surface antigen
positive) (2). Despite the fact that
it is preventable and treatable,
each year up to 1 million
people die from hepatitis B (1).
2. Look Into HBV
• Hepatitis B particle, also known as
Dane particle, have similar size as
other animal virus (3).
• The genome of HBV (3.2kb),
enveloped in the core particle in the
virus, is the smallest among DNA
viruses (4).
• The genome of HBV is partially
double-stranded, including a longer
negative strand and a shorter positive
strand (5).
• When HBV enters a hepatocyte, the
core particle disassembles and sends
the viral DNA into the nucleus of
hepatocyte where the viral DNA is
transformed into covalently closed
circular DNA (ccc DNA) (4).
• CccDNA serves as
transcription template in the
hepatocytes nucleus (6).
3. Why Hepatitis B Is Fetal
• According to the time lasting for this disease, HB can be divided into two subtypes.
• Acute HB lasts for less than 6 months and can be reversibly cured.
• Chronicle HB often lasts for longer time and will result in irreversible and lethal complications like
cirrhosis, hepatocellular carcinoma and liver failure (7). 6. Conclusion
• Although the spread of hepatitis B has been
Proteasome
controlled, the number of infected people in the
world is still a huge number. The efficacy of
Core Particle
traditional medicine is not satisfactory.
TRIM21 • The novel therapy developed a new way to
DNA Polymerase degrade certain protein in the cell with TRIM21
system as long as the antibody targeting that
protein can be produced; however, there is a
Lipid Bilayer Membrane
defect of the therapy that the cell-
penetrating antibodies can enter
Cell-penetrating
to any types of cells in human
Antibody
Viral DNA
-
5. New Ways To Eradicate HBV
• Recent research has discovered that our cells have a self-defense
+ HBx
system which can destroy the virus marked by the antibody via a
common way used to remove incorrectly folded proteins (10);
• TRIM21, a protein acting as both intracellular antibody effector and
E3 ubiquitin-protein ligase, is the core of cells' self-defense system
(10). It can recognize the antibody on the virus capsid and direct
4. The Limitation Of Current Therapies the virus to proteasome to degrade it (11);
• Hepatitis B Virus X protein is a multi-functional protein playing an
important role in the survival of HBV:
• HBV can’t be eradicated yet due to its properties and the limitations of current treating ① HBx is required to start and keep HBV replication after infection
technologies. (12);
• Interferon is widely used to treat virus infection including HB; however, it can only clear ② HBx can activate cccDNA by unscrewing the super spiral so that
out the virus in the blood. HBV often hide in the hepatocytes in the form of cccDNA RNA polymerase can bind to the cccDNA (13);
• In 2017, a research group from China used a cell-penetrating
(9), so existing drugs have no way to stop the transcription and translation of HBV. antibody targeting HBx to start TRIM21-mediated eliminating
• Vaccine is also used as a treatment to it. But as a virus, the HB virus can easily pathway and successfully stopped viral activities resulting in the
mutate especially under the influence of vaccine; loss of the surface antigen of HBV (14);
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Pathology. 1990; 22:26. 5. Cento V, Mirabelli C, Dimonte S, Salpini R, Han Y, Trimoulet P et al. Overlapping structure of hepatitis B virus (HBV) genome and immune selection pressure are critical forces modulating HBV evolution. Journal of General Virology. 2012;94(Pt_1):143-149. 6. Tong S, Li J, Wands J, Wen Y. Hepatitis B virus genetic variants: biological properties and clinical implications. Emerging Microbes &
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variants: biological properties and clinical implications. Nature. 2012 10. Mallery, D.L., McEwan, W.A., Bidgood, S.R., Towers, G.J., Johnson, C.M., James, L.C. & Fearon, D.T. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21), Proceedings of the National Academy of Sciences of the United States of America.2010;107(46): 19985-19990. 11. James, L.C., Keeble, A.H., Khan, Z.,
Rhodes, D.A. & Trowsdale, J. Structural Basis for PRYSPRY-Mediated Tripartite Motif (TRIM) Protein Function, Proceedings of the National Academy of Sciences of the United States of America. 2007;104(15): 6200-6205. 12. Lucifora J, Arzberger S, Durantel D, Belloni L, Strubin M, Levrero M, et al. Hepatitis B Virus X protein is essential to initiate and maintain virus replication after infection. Journal of hepatology.
2011;55: 996-1003. 13. Belloni, L., Pollicino, T., Nicola, F.D., Guerrieri, F., Raffa, G., Fanciulli, M., Raimondo, G. & Levrero, M. 2009, "Nuclear HBx Binds the HBV Minichromosome and Modifies the Epigenetic Regulation of cccDNA Function", Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 47, pp. 19975-19979. 14. Zhang, J., Xiong, H., Cao, J., Wang, S., Guo, X., Lin,
B., Zhang, Y., Zhao, J., Wang, Y., Zhang, T., Yuan, Q., Zhang, J. & Xia, N. A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway, THERANOSTICS. 2018;8(2): 549-562.