Viral evasion of host immunity

Question 1

What can acquired immune response be split into?

Answer 1

T cell - kill infected cells as they will present pieces of viral fragments on MHC/surface

B cell - antibodies that neutralise viral particles that stop spread to new cells and people.

Question 2

Why are all viruses vulnerable to T cell responses?

Answer 2

All viruses are obligate intracellular parasites so can be picked up by cellular immune response and processed into small peptides and presented on MHC class 1. Epitopes are seen by T cell response as foreign and come and kill viral infected cells helping to clear virus as less new viral particles are released.

Question 3

What is a disadvantage of cellular immune response?

Answer 3

Short lives although clears viral infection not relied on for long term memory.
Lasts a month or two and takes a while to re-activate.
Most vaccines rely on B cell response nowadays.

Question 4

Which part of the virus can be presented?

Answer 4

Any part of the virus can be targets for the cellular immune response.
E.g. viral structure, enzyme, non-structural protein.
Any internal viral protein can be targeted by T cell.

Question 5

How are internal viral proteins and surface antigens different?

Answer 5

Only T cells respond to internal viral proteins and they tend to vary a lot less than the surface antigens.
Can be conserved across different strains of the virus.

Question 6

For a virus to persist what must it do?

Answer 6

Must evade cellular immunity

E.g. family of herpes

Question 7

Describe viral regulation of MHC class 1 antigen presentation

Answer 7

Viral peptide synthesised in infected cell. Targeted into proteasome where it is cleaved to small pieces. TAP transporter on ER into ER where it can be picked up by MHC molecules in conjunction with b2 microglobulin.
They transport and mature through ER to golgi and to cell surface where presented.
Cytotoxic T cells that are surveying all cells of the body looking for abnormal peptide, binding in conjunction with CD8, release of nasty chemicals e.g. perforin
No new viral particles/peptides

Question 8

What is an example of a virus and it’s mechanism for blocking antigen presentation.

Answer 8

Herpes simplex

Produces ICP47 that stops TAP transporter, so foreign epitopes can’t be put into ER and bound to MHC.

Question 9

What are the 3 examples that evade antigen loading onto TAP?

This only happens when virus has ability to persist

Answer 9

EBV EBNA1 cannot be processed by the proteasome
HSV ICP47 blocks access of the processed peptide to TAP
CMV (cytomegalovirus) US6 stops ATP binding to TAP preventing translocation

Question 10

What are examples of how modulation of tapasin prevents MHC transport?

Answer 10

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 11

What are examples of how viruses can interfere with MHC presentation?

Answer 11

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

Question 12

How does the Human papillomavirus counter innate immunity?

Answer 12

Long term chronic infection, causes warts can go onto cervical cancer.
E6 and E7 protein of virus can overcome innate immune system by blocking JAK1/STAT pathway and STING respectively.
To prevent signalling to outside cells, E5 will prevent transport of loaded MHC to membrane.
There is variation in these proteins, different virulence of serotypes.

Question 13

Despite preventing MHC transportation what does our body do to recognise there is still something wrong?

Answer 13

All normal healthy cells display MHC at their surface thus, its absence would be indicative of a problem.

Question 14

What happens to cells that don’t display MHC?

Answer 14

NK survey healthy cells to ensure they have MHC 1.

If they don’t they kill that cell, NK are innate cells.

Question 15

How have some viruses evolved to counteract the NK cells?

Answer 15

Viruses encode MHC analogues(CMV gpUL40) or upregulate MHC.

Question 16

What is virus mediated immunosuppression using measles as an example?

Answer 16

Measles has learnt to express cells that express CD150 positive cells (immune cells). Infect memory T lymphocytes and kills them erasing immunological memory. Essentially resetting immune experience so become naive to diseases they’ve already overcame.
ANTI-VAX IS RINSING KIDS, MEASLES RINSING KIDS IN 21ST CENTURY

Question 17

What is neutralisation of virus?

Answer 17

Antibody biding to virus and block virus from blocking cells.
Goal of most vaccines?

Question 18

Why are some viruses so difficult to provide vaccines for?

Answer 18

Antigenic variation:
Continued evolution driven by antigenic pressure from host - influenza antigenic drift, HIV quasispecies due to length of time spent in host.

Question 19

What are different types of antigenic variation?

Answer 19

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 (common cold cause), 100s of serotypes, don’t change within person just a lot of them so never become immune to them all.
poliovirus = 3 serotypes trivalent vaccine needed,
Dengue = 4 serotypes 4 different components in vaccine with 4 different specificities of AB
Consequence for vaccination.

Question 20

What is the major antigen known as?

Answer 20

Haemagglutinin

Head and Stalk(embedded in membrane) domain

Question 21

Which part of Haemagglutinin do we make ABs for?

Answer 21

head

Question 22

Give an example of antigenic drift

Answer 22

Influenza A
H3N2 has evolved antigenic drift. Common site of AB binding I think…
Vaccine efficacy 23% for influenza

Question 23

Where do broadly neutralising ABs bind?

Answer 23

Bind to the stem region where sequence is not varied (thought to be crucial to the viral structure) but few of these antibodies are made.

Question 24

What are the strategies to stimulate bnAB production?

Answer 24

Skewing the AB response towards HA2 stalk region via:
Headless HA(Haemgglutinin)
Hyperglycosylating HA1 head domain so forced to go to stalk
Peptides against fusion peptide. and ectodomain

Question 25

What are ferritin based nanoparticles?

Answer 25

Displaying the HA on a ferritin nanoparticle to spread out HA to make stem region more accessible.

Question 26

Why is targeting stem region a good idea?

Answer 26

Allows for a universal cough virus to be produced as it can target the non-variable region.

Question 27

Describe sequential immunization?

Answer 27

Many HA with different heads that have same stalk

Question 28

Do any of these methods work?

Answer 28

NO L0000000L

Question 29

How do HIV env Spike gp120 resist neutralization?

Answer 29

Large spaces between spikes prevents AB cross-linking (both FAB regions can’t be bound) thus, efficiency is reduced.
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 - may not even work against others in your own body let alone a different strain.

Question 30

What is the idea with bnABs and HIV?

Answer 30

There ought to be vulnerable sites somewhere on GP160 molecule which is the same for everyone which would result in universal vaccine.
Elite controllers of HIV have made antibodies that bind to stalk region and these can be cloned out.

Question 31

What is the problem with bnABs with HIV?

Answer 31

Viral load is controlled by escape mutants do appear, AB doesn’t work very well after a short while in animals

Question 32

What is special about human rhinovirus?

Answer 32

There are hundreds of serotypes hence you’ll probably never be immune.

Question 33

What are the 2 different vaccines for Polio

Answer 33

Salk vaccine (inactivated virus coat)
Sabin vaccine (live attenuated)
BOTH must contain all 3 serotypes to ensure no circulating Polio.
One serotype has been eradicated.

Question 34

Summarise Dengue

Answer 34

There are 4 serotypes
Upon 2nd infection with 2nd serotype you get Dengue haemorrhagic fever. 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 iv fluid replacement.

Question 35

Why do you get Dengue Haemorrhagic fever?

Answer 35

AB against first dengue virus can be made to several different parts of capsid. Some will be good at neutralising but some will also bind to other serotypes but are not neutralising ABs so you end up with immune complexes of AB and virus which can be picked up by Fc receptor on macrophages and monocytes. Virus can actually be taken into immune cell and replicate within immune cell.
Increasing its tropism (number of cell types it can infect)
ANTIBODY DEPENDENT ENHANCEMENT OF DENGUE
Virus detected by PRRs as it tries to replicate which stimulates huge outburst of cytokines ILs and TNF-alpha and IFNs causing endothelial leakage.
Cytokine storm leads to the fever.
This makes vaccination dangerous EQUAL NEUTRALISING AB LOAD AGAINST ALL 4 SEROTYPES.

Question 36

Where does AB usually bind?

Answer 36

Spike glycoprotein on the HA.

Question 37

Which answer is not true?

Viruses that can’t control the innate immune system well might….

Answer 37

A: be useful as oncolytic agents
B: be difficult to grow in standard cell culture systems
C: be restricted at crossing the host range barrier and unlikely to spark outbreaks in other species
D: be useful as live-attenuated vaccines
E: be highly adapted to their host species

Question 38

Which is true?Viruses counteract activation of the interferon system by:

Answer 38

A: varying their coat protein sequences
B: encoding proteins that cleave or target host factors for degradation
C: preventing the loading of peptides by TAP
D: inducing a cytokine storm
E: encoding MHC homologues

Question 39

Which is true?

RNA viruses are more likely than DNA viruses to

Answer 39

A: code for proteins that interfere with innate immunity
B: code for proteins that interfere with cellular immunity
C: Have error prone polymerases that promote antigenic variation
D: Use lipid envelopes to protect their genomes that also contain host proteins that control complement activation
E: Activate interferon induction pathway through cGAS and STING.

Question 40

Which is NOT true concerning the interplay between Hepatitis C virus and the immune systems

Answer 40

A: Its E2 protein varies by more than 30% so antibodies only bind a tiny fraction of the viral quasispecies
B: T cell epitopes vary so that the virus is not cleared in the early stage of infection and this determines chronicity
C: NS3/4A protease cleaves MAVS and prevents activation of interferon
D: It encodes a protein called vif that counteracts the interferon stimulated gene APOBEC and prevent it from inducing hypermutation of the viral genome
E: A genetic polymorphism in IL28b results in non-responsiveness to interferon treatment