Micro 5: Viral evasion of host immunity

Question 1

How can the immune system detect viruses

Answer 1

Viruses are intracellular pathogens and so their proteins are easy targets for processing and presentation by MHC.

Question 2

What parts of the virus is an immune response mounted against

Answer 2

The MHC can present all parts of the viruses, not just the outside.

The antibodies will be made obviously to surface molecules

But the inside of the virus can be preseted on MHC and this can trigger CD8+ T cell to kill the virally infected cell

Question 3

What is more variable, internal viral proteins or surface molecles?

Answer 3

Internal viral proteins can be targets of cellular immunity. They tend to vary less than surface antigens.

Question 4

T/F a virus can be chronic without interfering with cellular immuity

Answer 4

F…

Viruses that persist must evade cellular immunity

Question 5

Give an example of a family of viruses that evade cellular immunity

Answer 5

. The family of herpes viruses are the classic examples.

Question 6

Outline presenation of internal peptides inside a cell

What is TAP

Answer 6

Proteins in cell chopped up by proteosome,

peptides transported into the ER where they are loaded onto MHC class 1 and the b2-microglobulin is added

This is then transported through the golgi apparatus and displayed on the surface of the cell

The peptide being presented can then be seen by a T cell receptor on a T lymphocyte

TAP is the protein used to translocated processed peptides from the proteasome into the rER for binding to MHC

Question 7

Which cells in th ebody expresses class 1 MHC

Answer 7

All

Question 8

What activates the T cell

Answer 8

The MHC 1, TCR, foreign peptide and CD8 is important too

Question 9

How do HSV 1 prevent interfere with cellular immunity

Answer 9

HSV ICP47 blocks access of the processed peptide to TAP

Question 10

How does EBV evade cellular immunity

Answer 10

EBV EBNA1 cannot be processed by the proteasome

so the viral protein cannot be chopped up and put into the ER so it cannot be presented in MHC class 1 to activate T cell

Question 11

What is the name of the protein that transports peptides into the ER

Answer 11

TAP

Question 12

How does CMV evade cellular immunity

Answer 12

CMV US6 stops ATP binding to TAP preventing translocation

CMV US3 binds tapasin and prevent peptides being loaded to MHC

(i.e. cuts off the energy to TAP so peptides can’t get into the ER and thus cannot be associated with the MHC molecules and cannot be presented to the T cells)

Question 13

Which molecule assists in loading the peptide onto the MHC

Answer 13

Tapasin

Question 14

How can adenovirus effect cellular immnity

Answer 14

Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum

Question 15

How does the KSHV (HHV8) evade cellular immunity

Answer 15

KSHV kK3 protein induces polyubiquitinylation and internalization of MHC.

From the internalized endosome, MHC is passed to lysosomes where it is degraded.

Cannot present viral proteins to the T cell

Question 16

What type of virus is the HPV

Answer 16

DNA virus, but with shorter genome than herpes

Question 17

How does HPV evade the immune response

Answer 17

Both cellular and innate response

Just note that because HPV has a small genome, its proteins often do diverse range of functions

E6/E7 are oncogenic (interfere with cell cycle), but they are also binding to proteins involved in the interferon detection pathway (cGAS, STING etc) and the IFN-a effector pathway (innate).

E7 also prevents transcription of MHC and TAP proteins

E5 holds onto the MHC class 1 molecule in the ER and the golgi and prevents it from being transported to the surface (cellular)….. BUT think about the consequence of loss of MHC

Question 18

What is the human response to lack of MHC on cells

Answer 18

This makes immune system think there is virus in the cell

So loss of MHC1 activates NK cells

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 19

How do viruses get around the NK response which kills them if they interfere with MHC

Give an example

Answer 19

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

Question 20

What are virus vaccines usually trying to achieve

Answer 20

An antibody response

Question 21

What is antigenic drift, vs antigenic shift

Answer 21

Continued rapid evolution driven by antigenic pressure from the host= antigenic drift

Introduction of new subtypes from animal source= antigenic shift

Question 22

Give example of antigenic drift and shift

Answer 22

Drift: influenza antigenic drift + HIV quasispecis

Shift: influenza antigenic shift

Question 23

What is a quasi species in relation to antigenic drift

What is the difficulty for treatment

Answer 23

It’s when HIV replicates inside you it and spits out lots of different variants of the virus (=antigenic drift)

The body can’t mount reponses against each subtype of the virus and contain it because of all of the different surface molecules

Question 24

Outline the differences in the number of serotypes with viruses and the consequences for vaccination

Answer 24

There is antigenic variation existing as different genetically stable serotypes that cocirculate in humans

Rhinovirus- 100s
Polivoris- 3
Dengue- 4

Consequence is theat the polio and dengue viruses nit to be trivalent and quadrivalent respectively

The rhnovirus it is impossible to get a vaccine to promote immunity against so many serotypes… and not worth it cos only common cold anyway

Question 25

What drives influencza antigenic change

Answer 25

EVOLUTIONARY PRESSURE DRIVES ANTIGENIC CHANGE IN INFLUENZA ABs bind to viruses and is neutralised

Question 26

What do ABs bind on influenza

Answer 26

Haemagglutinin= major influenza viral spike antigen It has head and stalk domain. A trimer

Question 27

Outline the conservation of haemagluttinin

Answer 27

There are some AAs which are highly conserved and some which are highly variable between different haemagglutinin molecules The head domain (which pokes out most into the external environment) is highly variable

Question 28

Why is the head domain likely to be variable in the haemagglutinin molecule

Answer 28

So that the B cells don't mount an immune response to it (i.e. the AA are constantly changing so that previously formed ABs cannot bind them) =ESCAPE. This is the basis of antigenic drift

Question 29

What is the head resonsible for in haemagluttinin

Answer 29

Binding to the cells influenza wants to infect (i.e. respiratory epithelium) The target of B cells to make antibodies against it =HA1

Question 30

How much do AAs have to change within the haemagglutinin molecule in order to prevent preformed AB binding

Answer 30

If the haemagglutinin has only a couple of AAs change, it will escape the preformed antibodues

Question 31

Which part of the haemagluttinin has conserved AAs and why

Answer 31

The stalk (=HA2) Maybe because the protein is so critical to the virus that it cannot be varied (not selected for) OR no evolutionary pressure yet (only a tiny fraction of the antibodies actually see the stalk, they se the head)

Question 32

How could a universal influenza be developed

Answer 32

Develop AB to the part of the haemagglutinin which is conserved and integral to its function and thus present on every haemagglutinin thus alowing us to target every strain of influenza

Question 33

How do we know whether we need to update flu vaccine

Answer 33

You look at the variable part of the haemagglutinin molecule on Influenza A virus H3N2 (which is the virus causing seasonal flu) To see if they have changed enough such that ABs produced from pre-administerd vaccines will not longer be specific enough to bind the haemagglutinin You look on antigenic cartography

Question 34

Why is it so difficult to vaccinate against influenza

Answer 34

H3N2 antigenic drift is rapid and many clades co-circulate

Question 35

Outline the process of deciding which flu vaccne to make

Answer 35

Collection of influenza samples from infected people, genetics (i. sequence them) and antigenic characterisation (incl antigen cartography), WHO recommends vaccine strains These vaccine strins are then grown in bulk When you do antigenic cartography, if the viruses are all very close together then you don't need to update the vaccine, but if the dots are diverging then you need to update

Question 36

What happens if the correct flu strain isn't chosen for vaccine

Answer 36

The selected strain could be a poor match with the predominant circulating virus. Low efficacy

Question 37

What area of haemagluttinin does 'broadly neutralising Ab' attack?

Answer 37

Broadly neutralising Ab (bnAb) attacking stem region

Question 38

Is the the bnAb currently used?

Answer 38

No, Current vaccines generate specific Ab responses raised against immunodominant HA1 epitopes at five antigenic sites (Sa, Sb, Ca1, Ca2, Cb) Basically the conserved regions of the haemagglutnin has been found but the immune system hasn't really developed many T cells against it because it doesn't see it enough (the head is the area exposed to the immune system) You need to get the immune system to see the conserved area if you want to develop the universal influenza vaccine that tackles all types of the virus

Question 39

Ideas for development of universal influenza vaccine (i.e development of the bnAb antibody which targets HA2?)

Answer 39

1. Headless HA 2. Hyperglycosylating HA1 head domain (so that the immune system can't see HA1 and just focuses on HA2) 3. Peptides against fusion peptide (FP) and ectodomain (EHA2) 4. Ferritin based nanoparticles displaying HA 5. Sequential immunization with Chimeric HA

Question 40

How could ferritin based nanoparticles work in influenza

Answer 40

displaying HA then allows more room for B cells to come in and but with more space etween HA molecules and this recognise the stalk part of the antigen which is usually hidden away

Question 41

How could Sequential immunization with Chimeric HA help to develop universal influezna vaccine

Answer 41

Could keep changing HA1 and keep HA2 conserved when giving booster vaccines This will make the immune system focus on the conserved part not the variable part

Question 42

Which part of HIV helps it to evade antibodies

Answer 42

HIV env spike gp120 resists neutralization

Question 43

How does gp120m the HIV spike molecule, evade neutralisation

Answer 43

1. Large space between spikes prevents Ab crosslinking 2. Extensive glycosylation masks antibody epitopes 3. Functionally important parts of the molecule are poorly accessible, CD4 binding site, redundant amino acids are visible to B cell receptor and antibodies. 4. Huge variation in the redundant amino acids means most antibodies are highly clade specific.

Question 44

Why can large spaces between spikes be a positive and negative thing for viruses

Answer 44

Problem for the virus: Allows lots of spaces for ABs to come in and bind the viral spike proteins (i,,e the basis for the ferritin nanoparticle influenza vaccine relies on this) Benefit for the virus: It means that Abs which bind the viral proteins are too far apart to cross link So Abs are less efficient

Question 45

What molecule is more glycosylated- gp120 or haeamagglutiin

Answer 45

gp120

Question 46

What type of molecule is gp120

Answer 46

trimer

Question 47

Do bnAbs exist for HIV?

Answer 47

bNabs produced as biological therapeutics can control viral load. but haven't yet been developed

Question 48

T/fAntibodies that can cross react with many HIV strains do exist alongside virus in people who control infection.

Answer 48

T

Question 49

bNab controls viral load but what is the problem with it

Answer 49

That the conserved regions in the gp120 may just mutate (i.e. it might be that they are not necessary for viral function, and that the virus just didn't have selective pressure before to chage those areas)

Question 50

Differentiate the antigenic drift in human rhinovirus with influenza

Answer 50

So the evolutionary process for the common cold virus happened many years ago but there are hundreds of serotypes With influenza, the process is still happening such that there are still new strains being produced The reason we cannot vaccinate for the common cold virus is that there are so many serotypes The reason we cannot vaccinate for flu is that there are new serotypes every year, and many strains cocirculate

Question 51

Outline the problems with the sabin vaccine for polio

Answer 51

For the live attenuated Sabin vaccine, administration of all 3 at once resulted in virus interference and poor response to one component. This meant that you could still be infected with the type against which the body didn't respond to in the vaccine However you just needed to adjust the ratios to increase the amount of weedy virus that you injected One serotype has been eradicated from the world so yu only really need the body to respond to two serotypes now anyway

Question 52

What is teh consequence of antigenic variation of denuge virus

Answer 52

Dengue haemorrhagic fever.

Question 53

What causes dengue haemorrhagic fever with regardto antigenic variation

Answer 53

Dengue Virus exists as 4 different serotypes. If you are infected with one serotype, you develop Abs to it But if a second serotype then infects you, then antibody generated against the previous serotype can bind but not neutralize the new serotype Instead, the Ab-new serotype complex binds to monocytes via the Fc receptor And the new serotype can then access the monocytes and replicate inside them!

Question 54

Why does infection of monocytes by a second dengue serotype infection lead to DHF

Answer 54

1. New tropism for the virus to grow in (rapidly grows) | 2. Because the monocyte is an APC, then it can release loads of cytokines and cause cytokine storm

Question 55

What does dengue haemorrhagic fever result in How is it detected Treatment

Answer 55

Leakage of blood plasma from capillaries (due to cytokine storm) 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 56

What receptor does measles use and thus what is its tropism

Answer 56

MV infects CD150 (=SLAM) positive cells, including memory lymphocytes and erases immunological memory.

Question 57

What is the longer lasting consequence of measles infecion

Answer 57

2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.