viral evasion of host immunity

Question 1

describe why viruses are effected by cellular immunity *

Answer 1

they are intracellular pathogens - so proteins in their structure, and the proteins they produce are easy targets for processing and presentation by MHC

the epitopes are seen as foreign; cells presenting the epitopes are killed by T cells before cell can release virus particles - this is cellular immunity

the internal viral proteins are conserved across strains/serotypes - they dont vary very much

Question 2

why is cellular immunity not used in vaccines *

Answer 2

it is short lived

Question 3

what is essential for viruses that persist *

Answer 3

they must be able to overcome the cellular immunity

Question 4

describe the mechanism of cellular immunity *

Answer 4

viral peptide is taken into a proteosome and cleaved

then transported into the ER by the TAP transporter

picked up by MHC and B2 micorglobin

goes through the golgi and is presented to the surgace

CD8 T cells look for foreign peptides - if they bind to a peptide/MHC on the cell surface they release chemicals eg perforin which kills cells so the cell cnat release any of the viral protein

Question 5

describe how EBV avoids cellular immunity *

Answer 5

EBNA1 is full of glycine so cant be chopped by the proteosome so invisible to the cell

Question 6

describe how HSV avoids cellular immunity *

Answer 6

ICP47 blocks access of the processed peptide to TAP - doesnt enter the ER

Question 7

describe how CMV avoids cellular immunity *

Answer 7

US6 stops ATP binding to TAP - preventing translocation

US3 binds tapasin (tapasin normally loads MHC) - prevents peptides being loaded into MHC

Question 8

describe how adenovirus avoids cellular immunity *

Answer 8

E3-19K prevents recruitment of TAP to tapasin and retains MHC in the ER

Question 9

how does KSHV (herpes virus 8/kaposi sarcoma herpes virus) avoid cellular immunity *

Answer 9

kK3 induces polyubiquitinylation and internalisation of MHC

this recycling of MHC stops it being on the cell surface

from the internalisd endosome the MHC is passed to the lysosome where it is degraded

Question 10

describe how human papilloma virus counters the innate immune response *

Answer 10

stops the STING pathway using E7 and E6 proteins

if there is IFN - E7 and 6 block the Jak STAT pathway

Question 11

how does human papilloma virus avoid cellular immunity *

Answer 11

E5 prevents presentation of MHC class 1 at surface by stopping transport of MHC and loaded peptide to the cell surface

Question 12

what is teh problem for viruses if they stop presentation of MHC molecules *

Answer 12

normal healthy cells display MHC class 1 at surface

cells that dont display MHC are detected by NK cells and killed - therefore viruses that disrupt MHC presentation are killed by NK

Question 13

how do viruses avoid NK cells *

Answer 13

the encode MHC analogues, eg CMV has gpUK40 (glycoprotein)

this is put on the surface of cells - fool NK that there is an MHC molecule and that the cell is healthy

Question 14

what determines the virulence of the virus *

Answer 14

where it is in the evolutionary arms race between host and virus

Question 15

describe neutralisation *

Answer 15

Ab from B cell bind virus - block them from entering cells

vaccines induce Ab to do this

Question 16

describe antigenic variation *

Answer 16

different forms of ag variation:

• continued rapid evolution driven by antigenic pressure from host - influenza antigenic drift (change is driven by the immune reponse), HIV quasispecies (present in the body for so long that it replicates and has many versions of itself - no need to change because there is a bad Ab response anyway
• introduction of new subtypes from animal source - influenza antigenic shift - look different to everyone’s immune system so no protection
• existing as different genetically stable serotypes that cocirculate in humans eg rhinovirus has 100 serotypes (never have immunity against all), poliovirus have 3, dengue have 4

Question 17

describe antigenic drift *

Answer 17

if have Ab against a specific virus that virus isnt going to replicate

as we develop Ab to one strain - the virus mutates and produces different Ag that we dont have Ab to

therefore the vaccine has to be updated every year

Question 18

describe haemagglutinin *

Answer 18

it is the major influenza viral protein

has a head domain and stalk domain

there is a lot of variation in the head domain - this is the bit that is seen by the Ab

the variation occurs because the virus mutates all the time because it has RNA polymerase that is error prone

Question 19

describe how we determine antigenic drift *

Answer 19

use antigenic cartography (study of maps) to see the variation between ag in virus over years - the further away the dots = more variation - when far enough apart they form clusters = need new vaccine because no cross reactivity anymore

also look at how fast the virus evolves - use phylogenetic tree - see that there are different groups of H3N2 flu virus that are evolving away from each other all the time

so look cartographically, genetically and at ag to see what should be the vaccine for the next year

Question 20

problem with ag drift for vaccine *

Answer 20

by the time developed vaccine - the ag have already changed from what predicted 6months earlier

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Question 21

what are the 2 types of Ab and their use in vaccines *

Answer 21

highly specific Ab - these are what are generated by current vaccines - they are specific Ab responses against HA1 epitopes at 5 antigenic sites

broadly neutralising Ab (bnAb) attack the stem domain of the Ag - work against all strains because this part of the ag cant change either because cant or because has no need to because no Ab against it

therefore we need to develop Ab to target the stalk so that we can get a universal flu vaccine - have to persuade the immune system to access the more inaccessible part of the Ag

Question 22

strategies to stimulate bnAb production *

Answer 22

need to fool the immune system to do something that it doesnt normally do - skew the Ab response to the HA2 stalk region:

• headless HA - mean Ab is forced to the bottom
• hyperglycosylating HA1 head domain - Ab forced to go to the bottom
• peptides against fusion peptide (FP) and ectodomain (EHA2)
• ferrotin based nanoparticles displaying HA so the haemagglutinin is more spread out so the stem is more accessible to B cell
• sequentially immunise with chimaric haemagglutinin- ie different heads but all the same stalk

none very effective

Question 23

describe how Ab evasion by HIV happens *

Answer 23

HIV spike gp120 resists neutralisation because:

• large space between spikes preventing Ab cross linking - therefore difficult to get Fab to bind to different spikes
• extensive glycosylation masks Ab epitiopes
• functionally important parts of the molecule are poorly accessible, CD4 binding site, redundant AA are visible to B cell receptor and Ab
• huge variation in AA mean most AB are class specific - wouldnt work against all the differnet types in the body

Question 24

describe broadly neutralising Ab to HIV *

Answer 24

Ab that can cross react with multiple strains do exist alongside virus in people who control infection

bNabs produced as biological therapeutics can control viral load

Ab against small region can neutralise several strains of HIV

however there are mutations so the bNabs dont work well after a while - so would have to update vaccine every week

Question 25

describe problem with vaccinating against rhinovirus *

Answer 25

causes common cold

there are >120 antigenically distinct serotypes that cocirculate - impossible to make vaccine against them all and nothing in common to target

Question 26

describe vaccination against poliovirus *

Answer 26

3 serotypes require a trivalent vaccine

for live attenuated vaccine admin of all 3 strains at once = virus interference and poor response to 1 component because it was outcompeted - meaning there was no immunity against 1 component

to adress this need to give a higher dose of the weaker serotype in vaccine

Question 27

describe dengue *

Answer 27

arbovirus - carried in mosquitoes

4 serotypes

1st infection of dengue = flu like symptoms - dont feel to bad

infection by 2nd serotype = dengue haemorrhagic fever = leakage of capillaries, low BP and RBC and protein level in blood - tendancy to severe bleeding and bruising

pt deteriorates even after fever stops = shock

treatment - IV fluid

Question 28

describe the mechanism of dengue haemorrhagic fever *

Answer 28

dengue exists as 4 serotypes

Ab generated against 1st serotype binds = neutralisation

if infection by 2nd serotype - Ab binds but doesnt cause neutralisation = formation of immune complex with virus and Ab

Fc of Ab binds to macrophages and monocytes - and is phagocytosed (tropism of virus is increased) = innate immune response - dengue is detected by the PRR = increased IL, INF type 1, TNFa - proinfammatory cytokines = endothelial leakage

Question 29

what is tropism

Answer 29

the number of cell types the virus can detect

Question 30

describe vaccines against dengue *

Answer 30

dangerous because needs to be able to neutralise all serotypes otherwise risk dengue haemorrhagic fever - make the situation worse

Question 31

describe measles *

Answer 31

measles infects CD150 (SLAM) positive cells - including memory lymphocytes and erases immunological memory = morbidity and mortality from other diseases - get diseases that you have already developed immunity to

therefore non-measles infections come under control when you have had measles vaccine - caused 90% reduction in childhood mortality in poorer settings

there is only 1 serotype of measles

Question 32

describe possible vaccine against coronavirus

Answer 32

against spike - little ag variation so can target the head

either by giving people RNA - get people to make active immune response

or put spike in chimp adenovirus - get people to develop immune response against this

problem is there is a risk SARS caused Ab dependant enhancement so need to ensure Ab causes neutralisation - perhaps explaining why older people do worse (they’re more likely to have seen previous coronavirus strain)

virus lasts in people for long time - suggesting it is avoiding the T cell immunity