Viral evasion of host immunity Flashcards
Why are viruses easy targets for processing and presentation by MHC? Hence, what does this make them vulnerable to?
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.
Describe the process of presentation of viral peptides on MHC Class I.
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
State three viruses (and the proteins involved) that evade antigen loading onto TAP.
- EBV:
- Expresses EBNA1 protein which cannot be processed by the proteasome - HSV:
- ICP47 protein blocks access of the processed peptide to TAP - CMV:
- US6 protein stops ATP binding to TAP preventing translocation
State two viruses (and the proteins involved) that modulate tapasin function and prevent MHC transport.
NOTE: tapasin is involved in loading MHC molecules
- Adenovirus
- E3-19K protein prevents recruitment of TAP to tapasin and retains MHC in the endoplasmic reticulum - CMV
- US3 protein binds to tapasin and prevents loading of peptides onto MHC
State one virus (and the protein involved) that interferes with MHC presentation at the cell surface.
KSHV (Kaposi Sarcoma Herpes Virus):
- kK3 protein induces polyubiquitination and internalisation of MHC => MHC is passed to lysosomes where it is degraded
How does Human papillomavirus counter the
- innate immune response
and
- cellular immune response?
- E6 and E7 proteins block the cGAS pathway.
- E5 protein prevents transport of loaded MHC to the cell surface for antigen presentation.
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?
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.
How do viruses evade this mechanism of NK-mediated killing infected cells?
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
What is antigenic drift?
Continued rapid evolution driven by antigenic pressure from the host
What is antigenic shift?
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
Explain how antigenic variation may lead to viral evasion of host immunity?
Viruses exist as different genetically stable serotypes that co-circulate in humans.
e.g. rhinovirus has more than 120 of antigenic ally distinct serotypes
How many serotypes of influenza are there?
4
How many serotypes of poliovirus are there and what type of vaccine was produced for polio?
3 – trivalent vaccine
NOTE: one of the serotypes has been eradicated now
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?
Haemagglutinin spikes
- Stalk domain (embedded in membrane)
- Globular head domain (antibodies bind here)
Which part of the Haemagglutinin spike of the influenza virus vary the most amongst different serotypes?
Globular head domain (constituent amino acids vary)
Describe the theory behind a potential universal influenza vaccine
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).
Describe strategies of synthetic vaccinology to stimulate bnAb production
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.
What is the viral spike/antigen on the surface of HIV?
Envelope glycoprotein GP120
Describe how the spikes on HIV resist neutralisation by antibodies
- 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.
Broadly neutralising antibodies to HIV?
- 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.
What are the features of dengue haemorrhagic fever (DHF)?
Leakage of plasma from capillaries leads to:
- Increased haematocrit
- Increased red cell count
- Decrease in protein
- Tendency to severe bruising and bleeding
What is the treatment for DHF?
IV fluids
How many serotypes of dengue are there?
4
Explain the significance of the presence of multiple serotypes of dengue with regards to the pathogenesis of DHF.
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
