26. Viral evasion of the adaptive immune response Flashcards
what are 4 things to remember about viruses and immunity interacting?
- every virus has a range of evasion mechanisms and they are all different
- host-virus balance can range from latency and non-cytopathic infection to cytopathic infection
- host responses need to be kept at bay long enough to allow the virus to replicate and infect another host
- a virus is inside the cell most of the time
what is the main viral defence?
the destruction of virally infected cells by CD8+ cells
what are the 4 ways viruses evade adaptive immunity?
- evasion of antibodies
- interference in antigen presentation
- infection of immune system cells
- latency
how do viruses enter host cells?
by binding to a receptor and either receptor mediated endocytosis or membrane fusion
how can antibodies prevent viral entry/infection?
- block the virus from interacting with the receptor - neutralising antibodies
- Prevention of conformational rearrangement once virus is bound
- interference with viral/host membrane fusion by locking virus structure in place
- blocking endocytosis
- prevention of capsule degradation
- antibodies taken up into cells to block other stages of the viral lifecycle
- Aggregation of viruses in the extracellular environment
how can viruses evade the antibody responses?
antigenic variation
steric inaccessibility of the receptor binding site
what 2 ways can the receptor binding site be blocked?
buried sites
glycan shields
how does antigenic variation occur in RNA viruses?
- RNA polymerase/reverse transcriptase has a very high error frequency
- no/limited proofreading ability
how is having no proofreading ability an advantage to the virus?
forms a cloud of quasispecies that allow different viruses within the infection to survive as they are better adapted
antigenic drift in both B and T cells
what happens in viral infection with non-neutralising antibodies?
- leads to virus entry in large amounts for some viruses
- viral advantage
- no selection pressure for the viral so viral proteins don’t need to change
- viral persistence
what could happen in viral infection with neutralising antibodies?
- selection pressure for mutants that can escape antibodies
- infection persistence
- reinfection of acute infection as acquired immunity diminished
what happens in viral infection with T cell recognition with intact epitope?
stays effective if the epitope doesn’t change
clearance of the virus
selection for escape mutants
what makes a T cell escape mutant?
Causes:
impaired processing for MHC presentation
decreases MHC binding
Reduced TCR binding
how can MHC expression be blocked?
if the peptide changes the MHC binding is impaired so antigen presentation is effected and impaired TCR recognition
what could happen if the T cell epitope doesn’t change?
over stimulation and exhaustion of the immune response
- up regulation of certain T cells and function is impaired
- persistent infection or cancer
what determines a viruses ability to evade vaccines and antibodies?
its plasticity
what viruses are not very effective at evading vaccines and antibodies?
not very plastic viruses like measles
means vaccines can last a long time
what causes plasticity?
we don’t know
what does a virus being very plastic mean?
they can change their protein/antigen structure fairly easily
what happens with antigenic variation at a genetic level?
some conserved regions which stay the same
hypervariable regions that are always mutating and changing
hypervariable genetic regions are often at antibody epitopes to make them ineffective
what is antigenic drift?
small mutations changing over time
existing immunity can continue working just not as well
what is antigenic shift?
a large dramatic shift that subverts all previous immunity
what regions tend to be conserved?
receptor binding domains
if these change binding will be affected
what can the mutations in the antigens be?
beneficial or deterimental
some changes can not benefit the virus but help it evade immunity
what is steric inaccessibility?
rest of the protein changes to block antibody engagement but the binding sites don’t change
what is the glycan shield hypothesis?
glycosylation levels change to prevent binding of neutralising antibodies but not receptor binding
how do levels of glycosylation change in the glycan shield hypothesis?
the mutations don’t change the structure but the pattern of glycosylation on the receptor
change the amino acid sequence changes the glycans present
constantly active and changes
what other receptor is heavily glycosylated?
SARS-CoV-2 spike protein
why are glycans not shown in diagrams?
because they are difficult to map and changes often
why is glycosylation not used as a therapeutic target?
even if the correct amino acids are present they may not always be glycosylated
what makes SARS-CoV-2 different from other coronaviruses?
the spike protein receptor is quite plastic and can change easily
what makes the SARS-CoV-2 spike protein plastic?
hypervariable receptor binding domain
ability to stabilise mutations which decrease receptor binding with complementary mutations that allow efficient binding again
these make it more transmissible
what do mutations in the N-terminal domain of the SARS-CoV-2 spike protein result in?
change how antibodies interact with the spike
changes elsewhere in the molecule to change the overall movement/fluidity of the molecule
how can viruses escape from T cells?
- infected cells present epitopes on MHC1
- antigenic shift stops peptide binding to MHC so no presentation
- OR antigenic drift means the peptide is still recognised but not a proper response is caused
- aberrant T cell response as the protein is not recognised correctly. incorrect cytokines secretion to make infection worse
- interference with the processing and presentation of peptides
how can viruses escape from NK cells?
- viruses downregulate MHC1 molecules
- some viruses with large genomes can encode their own decoy MHC1 to keep the inhibitory signal and prevent NK activation
- some viruses especially persistent viruses can affect or downregulate activating receptors
what is the normal MHC1 antigen presentation pathway?
- a cell infected with a virus making viral proteins and the proteasome degrades the proteins into peptides
- MHC are made and folded in the ER lumen
- viral peptides are taken into ER lumen by Tap 1 and Tap 2
- MHC interacts with Tap1/2 to pick up a viral peptide
- transported through the cell by the secretory system and inserted into the host cell membrane
how can MHC signalling be blocked?
- prevent proteins being degraded by the proteasome
- prevent peptide transport to the ER
- block transport of MHC mRNA out of the nucleus
- causes misfolding of proteins like MHC
- cause host proteins to be degraded by the endosome
- Down regulation
what proteins do MHC1 present?
any cytosolic protein
what proteins do MHC2 present ?
extracellular proteins processed by endocytic vesicles
what is the normal MHC2 presentation pathway?
- extracellular protein taken up into the endosome
- acidified endosome degrades protein into peptides
- MHC2 made in the ER membrane
- fusion vesicle of the MHC2 secretory vesicle and the vesicle with the viral peptides
- MHC2 picks up the viral peptide
- MHC2 present the antigen to activate other immune cells
what part of the MHC2 pathway does BPV-E5 block?
the acidification of the endosome so no activation of the proteases
what part of the MHC2 pathway does CMV US2 block?
block MHC2 transport from the ER
what part of the MHC2 pathway does EBV IL-10 block?
down regulate expression of MHC2 on the surface
what part of the MHC2 pathway does BPV E6 and HIV nef block?
prevents MHC2 peptide complexes from reaching the membrane and leaving the vesicle
what are some viral effects that interfere with MHC1 antigen presentation?
- MHC1 retained by ER
- MHC1 degraded by the proteasome
- viral peptides fail to enter the ER as Tap1/2 are blocked
- viral peptide block MHC1 in the ER
what are some viral effects that interfere with MHC2 antigen presentation?
- viral proteins resistant to proteasome degradation due to unusual sequences or phosphorylation
- MHC2 down regulated by viral IL-10 analogues
- MHC2 peptides not generated because endosome is not acidified
Human cytomegalovirus and immune evasion
large DNA virus with lots of mechanisms to avoid the immune system
- immune cell evasion
- cytokine homologues
- inhibit apoptosis
- up and down regulation
what viruses can infect the immune system?
HIV infects T cells and dendritic cells
Measles infects T and B cells and can wipe out your entire immune memory
Epstein-Barr virus infects B cells
what is Epstein Barr virus?
persistent viral infection
can cause other acute infections while infected like glandular fever
can cause B cell and epithelial cancers depending on genetics
what is the Epstein Barr virus pathway of infection?
- transmitted in saliva
- the virus probably infects epithelial cells
- then infects resting B cells in close contact with the epithelium
- large number of B cells get infected as the virus is very active
what kills EBV infected B cells?
CD8 T cells and NK cells
how common is latency in EBV?
1 in 100,000 B cells enters the latent state
what do latent EBV infected B cells do?
circulate in blood for years
express a very small number of proteins mostly for maintaining genomes
once the B cell is infected it becomes immortal
what is a use of EBV infected B cells?
they are immortal so they can be used in labs to study B cells and other B cell diseases
how do latent EBV infected cells become active?
unknown but possibly epithelial contact or immunosuppression
how can EBV lead to cancer?
by transforming epithelial cells
what does acute EBV infection lead to?
strong immune response
strong cytokine response
result in death of most infected B cells
what is the difference between EBV latency classes?
different latencies have different levels of gene expression and causes different types of cancers
