Infection 6: Hepatitis

Question 1

List 5 factors which affect the course of Hep B

Answer 1

Age at Infection

Immunosuppression

Host immune response

HBV genotype and mutations

Coexisting risk factor: Alcohol, HCV, HIV

Question 2

What are the main mechanisms by which Hep B establishes chronicity? [5]

Answer 2

1. HBV X- interferes with antigen processing and presentation
2. Foxp3 expressed on Tregs- downregulated HBV specific T cell response
3. PD1 (CD28)- upregulated so promotes apoptosis- downregulates virus specific T cell response
4. CTLA4- “immune off” switch when bound to CD 80 or CD86 on the surface of antigen-presenting cells. (no T cell activation)
5. IL10- anti-inflammatory so downregulates antiviral immune response

Question 3

Replication cycle of HBV [6]

Answer 3

1. Enters host cells
2. Viral polymerase completes positive strand of virus’ double stranded relaxed circular DNA (rcDNA)
   rcDNA→ ccDNA
3. ccDNA transcribed into viral mRNA by host RNA polymerase
4. Viral mRNA leaves nucleus and is translated into HBV core proteins and reverse transcriptase in cytoplasm
5. Viral mRNA and reverse transcriptase packaged into capsid and is reverse-transcribed into viral rcDNA
6. New viral DNA genomes are enveloped and leave cell as progeny virus

Question 4

How does IL-10 promote chronicity of HBV?

Answer 4

• Down regulates antiviral immune responses
  - CD4+ and CD8+ suppression with inhibition of IFN-γ and IFN-α production
  - Promotes apoptosis of plasmacytoid dendritic cells
• Attenuates inflammatory response but at cost of efficient antiviral immune responses

Question 5

Outline the mechanisms by which HCV establishes chronicity

Answer 5

1. High replicative rate and viral antigen load
   - CD8+/CD4+ anergic/exhausted: unable to proliferate/secrete cytokines
   - Display normal immune responses to other viruses
2. High error rate of RNA dependant RNA polymerase leading to mutations (quasispecies)
   - Escape neutralizing antibodies and cellular immune responses
3. HCV proteins interfere with immune response
   
   • NS proteins inhibit innate immune responses
     (recognition of TLR) through disruption of
     RIG-I signalling
   • Core protein down regulates IL-12 production
4. Neutralizing AB (core, envelope, NS3, NS4)
   develop too slowly, too late, short lived inducing HCV escape mutations

Question 6

Name 3 treatments for chronic HBV

Answer 6

1. Pegylated interferon
2. Tenofovir/Tenofovir alafenamide
3. Entecavir