4 - Viral Evasion of Host Immunity (05.03.2020)

Question 1

Viruses and cellular immunity

Answer 1

• Viruses are intracellular pathogens and so their proteins are easy targets for processing and presentation by MHC.
• Cellular immunity clears viral infection but is short lived.
• Internal viral proteins can be targets of cellular immunity. They tend to vary less than surface antigens.
• Viruses that persist must evade cellular immunity. The family of herpes viruses are the classic examples.

Question 2

What are viruses?

Answer 2

obligate, intracellular parasites

Question 3

What viral components are presented on MHCI molecules?

Answer 3

• structural peptides (e.g. surface proteins)
• non-structural peptides (e.g.enzymes, proteases)

B cells can only have surface proteins as their targets!

Question 4

Why do we rely on the B-cell response in vaccines?

Answer 4

• the cellular (T-cell) response is great but short lived.
• memory only lasts about 2 months
• vaccines rely on B-cell responses because memory is much longer

Question 5

How does the cellular immune repose work?

Answer 5

• virus enters cell
• viral peptides are broken down by a proteasome and then moved into the ER via a protein on the ER membrane
• MHC proteins are transcribed and translated and end up in the ER where they come together with the viral peptide
• the complex goes to the golgi
• then the complex is moved to the membrane
• cytotoxic t-cell uses TCR and CD8+ co-receptor to identify the presented peptide
• if abnormal, the T-cell is activated, releases proteins e.g. perforin and kills the cell
• this prevents the release of viral particles and

Many viruses have mechanisms to overcome parts of the host defence.

Question 6

Evasion of antigen loading to TAP

Answer 6

• EBV EBNA1 cannot be processed by the proteasome (because of many glycine and an unusual structure)
• HSV ICP47 blocks access of the processed peptide to TAP
• CMV US6 stops ATP binding to TAP preventing translocation

Question 7

TAP and tapasin

Answer 7

TAP = transporter associated with viral processing

Tapasin -> binds peptide onto MHC

Question 8

Modulation of tapasin function and prevention of MHC transport

Answer 8

• CMV US3 binds tapasin and prevent peptides being loaded to MHC
• Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum

Question 9

Interfering with MHC presentation at the cell surface

Answer 9

• KSHV kK3 protein induces polyubiquitinylation and internalization of MHC.
• From the internalized endosome, MHC is passed to lysosomes where it is degraded.

Question 10

KSHV

Answer 10

Kaposi’s sarcoma herpes virus

Question 11

How does HPV counter the immune system?

Answer 11

Human papillomavirus counters the innate immune response and the cellular immune response.

• e6 and e7stop STING/IR7 in interferon pathway (the cGAS / cytoplasmic DNA pathway)
• e6 and e7 also blocks Jak/stat pathway
• e5 protein prevents MHC1 presentation on infected cells

e6 etc are proteins made by the HPV

Question 12

How do viruses avoid NK killing by the missing self mechanism?

Answer 12

• 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.

= some viruses mimic MHCI molecules e.g. CMV -> T-cells don’t kill it because there is nothing specific for them to see and NK cells don’t kill it because there is something mimicking the MHC molecule.

Question 13

What happens if the cell does not present MHC1?

Answer 13

NK cells detect this and destroy that cell

Question 14

Red queen hypothesis

Answer 14

the hypothesis that organisms are constantly struggling to keep up with one another in an evolutionary race between predator and prey species.

-> humans evolve to protect from viruses, viruses evolve to infect humans

Question 15

Virus-mediated immunosuppression

Answer 15

• the measles vaccination is very good but some people don’t give it to children so it is still a problem
• measles vaccinaition has a much larger impact on childhood mortality than expected if it only protected from measles itself.
• Measles virus (MV) infects CD150 (SLAM) positive T-cells, including memory T-lymphocytes and erases immunological memory
• MV infection results in a 2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.

Question 16

Antigenic variation

Answer 16

-> this is why it is difficult to make vaccines for some diseases, the virus has a way to avoid the antibody mediated immune response

• 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
poliovirus, 3 serotypes
Dengue, 4 serotypes

• Evolutionary pressure drives influenza antigenic change

Question 17

Haemagglutinin

Answer 17

major influenza viral antigen

• has a head and a stalk domain: our antibodies react to the head domain (this is what mainly changes when the flu evolves)

Question 18

Antigenic cartography

Answer 18

• you take ABs from people that had the flu last year
• see if the ABs capture the AGs on the new strain of flu
• create a map of which parts / amino acids have changed
• map = dots -> the further away from each other the more distant they are antigenic ally speaking
• when they get too far away they build a cluster.

Question 19

Influenza vaccine - getting it wrong

Answer 19

• 2014/15 reported low vaccine efficacy against the H3N2 seasonal influenza (23% vs usual 65%).
• The selected strain (selected almost one year earlier) was a poor match with the predominant circulating virus.

-> people collect info on virus, antigenically, genetically, create maps and phylogenic trees and then the decision is made how the vaccine is designed (WHO involvement in some form) and it takes about 6 months for it to be ready and by then the flu virus will have changed.

Question 20

broadly neutralising ABs to the flu

Answer 20

• bind to the stalk region of the haemagglutinin
• work for all flu strains
• the question is if the stalk does not change because it doesn’t have to because there isn’t selective pressure or because a change there would be crippling to the virus

you would have to synthetic vaccinology

• you have to fool the IS to do sth it doesn’t usually do
• e.g. make haemagglutinin without head or cover the head with sugars so it recognises the stalk
• or you could display the HG in a different way so that they are spread out better and more accessible
• or sequential immunisation with different heads but same stalks

these approaches are being tried now (non working at the moment, lots of money put into there)

-> UNIVERSAL FLU VACCINE

Question 21

AB evasion by HIV

Answer 21

HIV env spike gp120 resists neutralization because:

• Large space between spikes prevents Ab crosslinking (the HIV virus is ‘bald’) -> doesn’t have many spikes and it is very difficult fora an AB to bind with both Fab regions (poor efficiency of neutralisation)
• 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.

Question 22

Broadly neutralizing antibodies to HIV

Answer 22

• looking for a part of the virus that is the same in all strains
• 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 (most of them bind to the stalk region) BUT after such therapy the virus can mutate in the host and another quasispecies becomes more dominant

Question 23

quasispecies

Answer 23

• A viral quasispecies is a population structure of viruses with a large numbers of variant genomes (related by mutations).
• Quasispecies result from high mutation rates as mutants arise continually and change in relative frequency as viral replication and selection proceeds.

Question 24

Human rhinovirus subtypes

Answer 24

• exists as hundreds of serotypes
• Human rhinoviruses cause the common cold.
• They exist as more than 120 antigenically distinct serotypes that co circulate.
• Impossible to make a vaccine against them all!

Question 25

Poliovirus vaccination

Answer 25

• Poliovirus has 3 serotypes
• Type 1 has been eradicated. Type 2 almost, however still difficult to reach places like Syria with vaccination.
• Sabin = live-attenuated (oral) -> the problem was that sometimes one of the 3 types got good immunity and the othes didn’t. You have to make sure that all 3 replicate equally well and that you are protected from all 3 strains.
• Salk: inactivated virus coat (good AB response)

=> both vaccine types have to be against all 3 serotypes

Question 26

Consequence of antigenic variation of Dengue virus

Answer 26

• 4 serotypes
• spread by mosquitoes
• the first time you get flu like symptoms
• the second time you can get Dengue Hemorrhagic fever
• DHF Responsible for 500,000 hospitalizations each year with 5% fatalities.
• Leakage of blood plasma from capillaries.
• Detected by increase in RBC count and decrease in protein level in blood.
• Tendency to severe bruising, and bleeding.
• Patient deteriorates even after fever drops; shock.
• Treat with iv fluid replacement.

Question 27

Why does dengue haaemorrhagic fever happen in a second infection?

Answer 27

• the ABs can bind but not neutralise the new serotype
• there are immune complexes (AB and AG) in the blood
• bind to Fc receptor on macrophaages
• engulfed by macrophages
• detected by PRRs in macrophages -> release of cytokines, increases vessel leakage, cytokine storm
  => AB dependent enhancement (ADE) of dengue

Question 28

Tropism

Answer 28

the number of different cell types a virus can infect

Question 29

What is the problem with making a vaccine for Dengue virus?

Answer 29

• there are four subtypes
• you would have to immunise to call 4 equally to prevent the consequence of dengue haemorrhage fever
• it is dangerous if not all are neutralised
• if you were to vaccinate children with a suboptimal vaccine you might just feast forward to the increased vulnerability / more susceptible state to DHF

Question 30

Human coronaviruses

Answer 30

• OC43
• 229E
• NL63
• HKU-1
  the top ones cause 10% of colds every year.
• SARS
• SARS-CoV2
• MERS
• COVID-19