viral evasion of host immunity Flashcards
describe why viruses are effected by cellular immunity *
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
why is cellular immunity not used in vaccines *
it is short lived
what is essential for viruses that persist *
they must be able to overcome the cellular immunity
describe the mechanism of cellular immunity *
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
describe how EBV avoids cellular immunity *
EBNA1 is full of glycine so cant be chopped by the proteosome so invisible to the cell
describe how HSV avoids cellular immunity *
ICP47 blocks access of the processed peptide to TAP - doesnt enter the ER
describe how CMV avoids cellular immunity *
US6 stops ATP binding to TAP - preventing translocation
US3 binds tapasin (tapasin normally loads MHC) - prevents peptides being loaded into MHC
describe how adenovirus avoids cellular immunity *
E3-19K prevents recruitment of TAP to tapasin and retains MHC in the ER
how does KSHV (herpes virus 8/kaposi sarcoma herpes virus) avoid cellular immunity *
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
describe how human papilloma virus counters the innate immune response *
stops the STING pathway using E7 and E6 proteins
if there is IFN - E7 and 6 block the Jak STAT pathway
how does human papilloma virus avoid cellular immunity *
E5 prevents presentation of MHC class 1 at surface by stopping transport of MHC and loaded peptide to the cell surface
what is teh problem for viruses if they stop presentation of MHC molecules *
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
how do viruses avoid NK cells *
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
what determines the virulence of the virus *
where it is in the evolutionary arms race between host and virus
describe neutralisation *
Ab from B cell bind virus - block them from entering cells
vaccines induce Ab to do this
describe antigenic variation *
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
describe antigenic drift *
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
describe haemagglutinin *
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
describe how we determine antigenic drift *
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
problem with ag drift for vaccine *
by the time developed vaccine - the ag have already changed from what predicted 6months earlier
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what are the 2 types of Ab and their use in vaccines *
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
strategies to stimulate bnAb production *
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
describe how Ab evasion by HIV happens *
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
describe broadly neutralising Ab to HIV *
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
