Viral evasion of host immunity Flashcards
Give examples of viruses that evade antigen loading to TAP.
EBV- EBNA1 cannot be processed by the proteasome.
HSV- ICP47 blocks access of the processed peptide to TAP.
CMV- US6 stops ATP binding to TAP preventing translocation.
Give examples of viruses that modulate tapasin function and prevent MHC transport.
CMV- US3 binds tapasin and prevents peptides being loaded to MHC.
Adenovirus- E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum.
Give examples of viruses that interfere with MHC presentation at the cell surface.
KSHV- kK3 protein induces polyubiquitinylation and internalisation of MHC.
From the internalised endosome, MHC is passed to lysosomes where it is degraded.
How do viruses avoid NK killing by the missing self mechanism?
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.
Viruses encode MHC analogues (CMV gpUL40) or upregulate MHC.
How can knowledge about how viruses manipulate infected cells be used to improve medical outcomes?
Human cytomegalovirus HCMV infects 60-90% of people and is only a problem in immunocompromised.
HCMV infection is a frequent problem for transplant recipients while they are immunosuppressed.
Usually seen in the first 30 days after transplant.
The virus needs to be eliminated from bone marrow cells of a transplant recipient before transplantation otherwise it will reactivate.
Quantitative proteomics reveals changes in cell surface in HCMV latently infected cells.
UL138 protein leads to loss of MRP-1, a molecule that can transport toxic substances out of the cell, from the infected cell surface.
This is evident even in latently infected cells.
Loss of MRP-1 transporter leads to accumulation of certain molecules in the infected cells including the toxic drug vincristine.
Cells from donors could be vincristine-treated before transplantation to eliminate HCMV.
What is antigenic variation? Give examples.
Continued rapid evolution driven by antigenic pressure from host: influenza antigenic drift, HIV quasispecies.
Introduction of new subtypes from animal source: influenza antigenic shift.
Existing as different genetically stable serotypes that cocirculate in humans.
e. g. rhinovirus, 100s of serotypes
e. g. poliovirus, 3 serotypes
e. g. Dengue, 4 serotypes
Consequence for vaccination.
What drives influenza antigenic change?
Evolutionary pressure.
How does HIV evade antibodies?
HIV env spike gp120 resists neutralisation because:
- large space between spikes prevents Ab crosslinking
- extensive glycosylation masks antibody epitopes
- functionally important parts of the molecule are poorly accessible, CD4 binding site, redundant amino acids are visible to B cell receptor and antibodies
- huge variation in the redundant amino acids means most antibodies are highly clade specific
What are 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.
What are human rhinoviruses?
Human rhinoviruses cause the common cold.
They exist as more than 120 antigenically distinct serotypes that cocirculate.
Impossible to make a vaccine against them all.
Discuss the poliovirus vaccine.
Three serotypes of poliovirus required a trivalent poliovirus vaccine.
For the live attenuated Sabin vaccine, administration of all 3 at once resulted in virus interference and poor response to one component.
One serotype has been eradicated from the world.
What is Dengue virus and the consequence of its antigenic variation?
Dengue haemorrhagic fever.
Responsible for 500,000 hospitalisations each year with 5% fatalities.
Leakage of blood plasma from capillaries.
Detected by increase in red cell count and decrease in protein level in blood.
Tendency to severe bruising, and bleeding.
Patient deteriorates even after fever drops, shock.
Treat with i.v. fluid replacement.
What is antibody dependent enhancement of Dengue?
Dengue virus exists as 4 different serotypes.
Antibody generated against a previous infection can bind but not neutralise, and lead to ADE, causing Dengue haemorrhagic fever.
How does the Ebola virus evade the antibody response?
Some viruses have glycoprotein antigens that are so heavily glycosylated (mucin like) that antibody access is hindered, e.g. HIV, Ebola.
Viral filaments might be harder for antibodies to neutralise as GP inaccessible in folded pockets (EBOV).
What is the role of sGP (soluble glycoprotein) in Ebola evasion of antibody?
Soluble GP is the default coding for the GP gene.
Full length GP is made by polymerase stuttering.
sGP is an antibody decoy.
sGP is immunosuppressive, inhibits neutrophils.
Reston virus version only suppressive in macaques.
