Viral evasion of host immunity

Question 1

Why are viruses easy targets for processing and presentation by MHC? Hence, what does this make them vulnerable to?

Answer 1

Viruses are obligate intracellular pathogens, and so internal viral proteins can be presented in the context of MHC at the cell surface.

Vulnerable to cellular immunity => can clear viral infection but is short lived.

Question 2

Describe the process of presentation of viral peptides on MHC Class I.

Answer 2

Viral peptides are 'chopped up' by the proteasome 
These peptides are then fed through the TAP protein into the endoplasmic reticulum 
In the endoplasmic reticulum, it will be loaded onto an MHC class I molecule and it will then move to the cell surface where T cells can recognise the antigen

Question 3

State three viruses (and the proteins involved) that evade antigen loading onto TAP.

Answer 3

1. EBV:
   - Expresses EBNA1 protein which cannot be processed by the proteasome
2. HSV:
   - ICP47 protein blocks access of the processed peptide to TAP
3. CMV:
   - US6 protein stops ATP binding to TAP preventing translocation

Question 4

State two viruses (and the proteins involved) that modulate tapasin function and prevent MHC transport.

Answer 4

NOTE: tapasin is involved in loading MHC molecules

1. Adenovirus
   - E3-19K protein prevents recruitment of TAP to tapasin and retains MHC in the endoplasmic reticulum
2. CMV
   - US3 protein binds to tapasin and prevents loading of peptides onto MHC

Question 5

State one virus (and the protein involved) that interferes with MHC presentation at the cell surface.

Answer 5

KSHV (Kaposi Sarcoma Herpes Virus):

- kK3 protein induces polyubiquitination and internalisation of MHC => MHC is passed to lysosomes where it is degraded

Question 6

How does Human papillomavirus counter the
- innate immune response
and
- cellular immune response?

Answer 6

• E6 and E7 proteins block the cGAS pathway.

- E5 protein prevents transport of loaded MHC to the cell surface for antigen presentation.

Question 7

What do NK cells recognise on the cell surface that triggers killing of cells? What impact does this have on viruses that disrupt MHC presentation?

Answer 7

Normal healthy cells display MHC at their surface.
Cells that don’t display MHC are detected by NK cells and killed.
Viruses that disrupt MHC presentation would end up being killed by NK cells.

Question 8

How do viruses evade this mechanism of NK-mediated killing infected cells?

Answer 8

Viruses encode MHC analogues (e.g. CMV encodes glycoprotein UL40) – virally encoded MHC is useless but it fools the NK cells

Or they up-regulate MHC

Question 9

What is antigenic drift?

Answer 9

Continued rapid evolution driven by antigenic pressure from the host

Question 10

What is antigenic shift?

Answer 10

Introduction of new subtypes of the virus from an animal source
NOTE: when they come from an animal source, the antigens don’t look like anything that humans have seen before

Question 11

Explain how antigenic variation may lead to viral evasion of host immunity?

Answer 11

Viruses exist as different genetically stable serotypes that co-circulate in humans.
e.g. rhinovirus has more than 120 of antigenic ally distinct serotypes

Question 12

How many serotypes of influenza are there?

Answer 12

4

Question 13

How many serotypes of poliovirus are there and what type of vaccine was produced for polio?

Answer 13

3 – trivalent vaccine

NOTE: one of the serotypes has been eradicated now

Question 14

State the major antigen on the surface of influenza to which antibodies bind. What are its to domains, and identify which domain the antibodies bind to?

Answer 14

Haemagglutinin spikes

• Stalk domain (embedded in membrane)
• Globular head domain (antibodies bind here)

Question 15

Which part of the Haemagglutinin spike of the influenza virus vary the most amongst different serotypes?

Answer 15

Globular head domain (constituent amino acids vary)

Question 16

Describe the theory behind a potential universal influenza vaccine

Answer 16

Current vaccines generate highly specific antibodies which bind to the head of the antigen, instead we engineer a vaccine which generates Broadly Neutralising antibodies (bnAbs) which attack the stalk domain of the antigen (which is much less variable among serotypes).

Question 17

Describe strategies of synthetic vaccinology to stimulate bnAb production

Answer 17

Via:

• Headless Haemagglutinin
• Hyperglycosylating head domain
• Ferritin based nanoparticles displaying haemagglutinins which are more spread out form each other and therefore the stalk region is more accessible.

=> antibodies have no choice but to be raised against the stalk region.

Question 18

What is the viral spike/antigen on the surface of HIV?

Answer 18

Envelope glycoprotein GP120

Question 19

Describe how the spikes on HIV resist neutralisation by antibodies

Answer 19

• Large space between spikes prevents Ab crosslinking
• Extensive glycosylation masks antibody epitopes
• ## Functionally important parts of the molecule are poorly accessible, CD4 binding site, whereas redundant amino acids are visible to B cell receptor and antibodies.

Question 20

Broadly neutralising antibodies to HIV?

Answer 20

• Antibodies that can cross react with many HIV strains do exist alongside virus in people who control infection.
• bNabs produced as biological therapeutics can control viral load.
• But note that the virus would eventually evolve to escape the bnAbs.

Question 21

What are the features of dengue haemorrhagic fever (DHF)?

Answer 21

Leakage of plasma from capillaries leads to:

• Increased haematocrit
• Increased red cell count
• Decrease in protein
• Tendency to severe bruising and bleeding

Question 22

What is the treatment for DHF?

Answer 22

IV fluids

Question 23

How many serotypes of dengue are there?

Answer 23

4

Question 24

Explain the significance of the presence of multiple serotypes of dengue with regards to the pathogenesis of DHF.

Answer 24

Infection with one serotype will cause antibody production.
Antibodies generated against this serotype will bind to but NOT neutralise any other serotype of dengue virus following subsequent infection.
=> the virus is then shuttled into a macrophage infecting it.
This is called ANTIBODY DEPENDENT ENHANCEMENT (ADE) causing Dengue Haemorrhagic Fever

Question 25

Measles virus infects what cells? and with what consequence?

Answer 25

MV infects CD150 positive cells, including memory lymphocytes and erases immunological memory => morbidity and mortality from other diseases