Virus Infections of the liver

Question 1

Hepatitis A

Answer 1

• oral transmission (contaminated food, water)
• vaccine: inactivated vaccines
• simpler in pathogenesis
• quickly cleared once immune system kicks in

Question 2

Hepatitis B

Answer 2

• serum and sexual transmission
• long incubation period
• assoc. w/ heptocellular carcinoma
• vaccine: subunit vaccine
• infection may be acute, fulminant (cytotoxic t cell destruction of hepatocytes), chronic persistent or chronic aggressive, some people become carriers

Question 3

Vaccines

Answer 3

• vaccines for Hep A and Hep B

- emphasis on prevention for Hep C and E

Question 4

Hepatitis mechanisms of disease

Answer 4

• replication in liver hepatocytes
• viremia
• generally not cytolytic, tissue damage due to cell mediated immunity
• Hep B and C cause chronic infections which can lead to hepatocellular carcinoma

Question 5

Hepatitis C virus genome encoded polyprotein products

Answer 5

• differential distribution of glycoproteins vs NS proteins-ensures that when virus buds Ns on inside and envelope proteins on outside
• NS3 is important component of protease, complexes and becomes active
• NS5 is polymerase, B is polymerase, A is more involved in binding template

Question 6

HCV phylogeny (5)

Answer 6

• course and severity depends on infecting virus genotype
• HCV strains vary in responsiveness to interferon therapy
• heterogeneity has implications for vaccine development-antigens from various serotypes may be necessary for broad protection
• RdRp lacks 3’-5’ exonuclease proofreading activity
• HCV types 1, 2, 3 widely distributed, 1a and 1b are most common

Question 7

HCV receptors

Answer 7

4 receptors currently known

• CD81
• SRB1-binds certain forms of lipoproteins
• CLDN1 and occludin-localized at tight junctions b/w cells, located on hepatocyte membrane

Question 8

Challenges to HCV vaccine development (4)

Answer 8

• virus diversity in envelope proteins-difficult to select ideal epitope
• difficulties in growing HCV in cell culture
• difficulties in assaying immune markers of protection
• lack of animal models

Question 9

Challenges to HCV vaccine development-Difficulties in assaying immune markers of protection

Answer 9

• neutralization of binding (NOB) assay (blocking of gpE2 binding to CD81)-a quick assay to determine the neutralizing ability of an Ab to glycoprotein E2
• high NOB titers correlate w/ spont clearance of HCV
• low NOB titers assoc. w/ long term HCV progressors

Question 10

Challenges to HCV vaccine development-lack of animal models

Answer 10

• closest model has been chimpanzee which allows vrep but does not develop hepatitis
• SCID mouse w/ human plasminogen activator, transplanted w/ human hepatocytes
• humanized mice
• transgenic mice with CD81, occludin

Question 11

HCV vaccine development

Answer 11

-no vaccine

Question 12

HCV replication cycle and antivirals

Answer 12

• most succesful antivirals are against protease or polymerase
• many immunomodulatory molecules undergoing testing (e.g. interferons, IL10, IL12, TLR agonists