1. Persistence of Hepatitis B Virus
Sandra Choi
MSc student in Dr. Lyle Mckinnon Laboratory
University of Manitoba
Block Lecturer: Dr. Alberto Severini

2. Hepatitis B infection Five hepatitis viruses: Hepatitis B virus (HBV)
Most common viral infection
2015: 257 million chronically infected people
- 0.8 million deaths
257 million: 3.5% population

3. HBV structure Family: Hepadnaviridae Enveloped + Nucleocapsid
DNA Virus
Partial double stranded
relaxed circular DNA (RCDNA)
Minus External strand: Up to
45% longer than internal
plus strand
Singh et al, 2015

4. HBV entry mechanism Targets liver hepatocytes because of receptors:
heparan sulfate proteoglycans
Sodium taurocholate co- transporting polypeptide
Yuen et al, 2018

5. Location+ Transmission Trends1
Modes of transmission:
High Endemic Regions: Infected mothers to infants
Low Endemic Regions: Sexual contact
Infected blood
Others… 2
High endemic areas- Mother to infected kids
High Risk Behaviours
2.Sex- high number of of sexual partners, number of STDs MSM,
3. Injections, transfusions, drug use…
4. Surgery, denstist, organ donations…
(WHO, 2017)

6. HBV Vaccine Successful creation in 1992- 95% efficacy
By Global implementation: 183 counties
High endemic regions
- Vaccines for >5 years old (since 90% develop chronic HBV)
Canada: ENGERIX®-B, RECOMBIVAX HB®, TWINRIX® and INFANRIX hexa™
- Doses and age vary by province
Manitoba: 2 doses in grade 6
Producing primary neutralizing antibodies is 95%.

7. Acute vs. Chronic HBV infections
Acute infection: Less than 6 months, Chronic: More than 6 months
HBsAg- Main clinical determinant
95% adults clear their acute infection
Acute infection Chronic infection
Trepo et al, 2014

8. Chronic HBV infections
Four stages: 1 2 3 4
Yuen et al, 2018

9. Symptoms and Disease Progression
HBV is mainly asymptomatic (Only 5% know their infection status)
Initial symptoms: Fever, fatigue, stomach pain
Acute HBV: Generic flu symptoms/ Asymptomatic
Minimal damage  Fulminant hepatitis (severe liver damage)
Chronic HBV: Generic flu symptoms/ Asymptomatic for years
Minimal damage  Liver cirrhosis and Hepatocellular carcinoma ( 25% mortality if untreated)

10. Host : Innate Immune Response
Innate Immune cells: Natural Killer (NK) cells, Natural Killer T (NKT) cells, macrophages/ Kupffer cells, dendritic cells (DC)
Macrophage, NK, NKT :Release Interferon (IFN) ϒ and Tumor necrosis factor (TNF)- α
Macrophage- Antigen presenting cells
NK cells- Cell to cell killing of infected hepatocytes
NKT cells- Activate NK cells
DC- IFNα and β
Yuen et al, 2018

11. HBV: Innate Immune Evasion
Supressing IFN ϒ and TNF- α
Macrophage- HBeAg decreases TLR-3 expression
NK cells- Increasing inhibitory receptors (ex.NKG2A) downregulating activating receptors (ex.CD16), HBcAg and HBeAg inducing cytokine IL-10.
NKT cells- Not fully understood
DC- HBsAg upreglating SOCS-1, blood dendritic cell antigen 2
Yuen et al, 2018

12. Host Adaptive Immune Response
Main effector cells: Cytotoxic CD8+ T cell (CTL)
CTL releases granzymes and perforins to destroy infected hepatocytes
T-regulatory cells: Modulate T- helpers and CTL
Yuen et al, 2018

13. HBV: Adaptive Immune Evasion
HBV suppression of IFN ϒ and TNF- α
Interfering with macrophage-CTL costimulatory receptors CD86 and CD28
Upregulation of Programmed cell death-1 (PD-1)
HBsAg polymerize to avoid antigen presentation
T-regulatory inhibition
Yuen et al, 2018

14. HBV DNA integration
HBV has other modes of persistence : Insertion of DNA into host genome
10% nucleocapsids contain linear dsDNA
Insertions of HBx open reading frame associated with disease progression
5-10% develop hepatocellular carcinoma

15. HBV Treatments Monitoring and surveillance - Blood and liver biopsies
Managing lifestyle
Treatment options:
Nucleos(t) ide analogues – Inhibit viral replication by preventing reverse transcription of DNA
- Examples: Tenofovir, Lamivudine
2. Interferon Therapy- Injections of interferon
(WHO,2017)

16. Future of HBV Persistence
Incidences are on the rise: 1.1million deaths (2000) to 1.3million deaths (2015)
WHO Agenda for Sustainable Development: Eliminate hepatitis as a global threat by 2030
Reduction of all hepatitis viral infections
Affordable care
Treatment
Education
Increasing vaccination (To 90% of population)
Increasing awareness from 5% to 90%

17. QUESTIONS?

18. References: Images
Singh, Jagtar & Sinha, Shweta. (2015). Volume-6, Issue-3, July-Sept-2015 Coden IJABFP-CAS-USA st st Received: 21 May-2015 Revised: 31 May International Journal of Applied Biology and Pharmaceutical Technology
World Health Organization. Global Hepatitis Report, 2017 (WHO, Geneva, 2017)
Trépo, C., Chan, H., & Lok, A. (2014). Hepatitis B virus infection. The Lancet, 384(9959), 2053–
Yuen, M., Chen, D., Dusheiko, G., Janssen, H., Lau, D., Locarnini, S., … Lai, C. (2018). Hepatitis B virus infection. Nature Reviews. Disease Primers, 4,