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Virology 11-20 > #20 viral evasion of cellular immune responses > Flashcards

#20 viral evasion of cellular immune responses Flashcards

1
Q

what are the two types of ways that viruses evade immune attack?

A

1) not being recognised by the immune system

2) interfering with functioning of particular immune mechanisms

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2
Q

what viruses are good at evading the immune response

A

Large DNA viruses such as poxviruses and Herpesviruses

they can encode a lot of weaponry

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3
Q

how does Herpesviruses evade the immune response?

A
  • it hides latent
    EBV hides in b cells
    HSV hides in neurons
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4
Q

how do viruses avoid detection by T-cells and Ab’s

A

antigenic drift and shift

done by influenza and HIV

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5
Q

what are ways of interfering with T-cell priming by DCs?

A
  • blocking TLR signalling to T-cell
  • interfere with DC maturation
  • interfering with naive t-cell population
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6
Q

how to avoid t-cell recognition

A
  1. antigenic variation in t-cell epitopes (influenza and HIV)
  2. inhibition of processing and presentation of viral peptides
  3. decreased production of MHC
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7
Q

how to avoid NK cell activation

A
  1. mutations in the ligand for the activating receptor
  2. virus encoded MHC-I like molecules
  3. upregulation of non-classical MHC molecules
    CMV does all of these
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8
Q

how can viruses interfere with cytokines??

A
  • encode virus cytokine homologues
  • redirect the t-cell response
  • block intracellular cytokine production
  • intracellular interference with cytokine function
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9
Q

how can viruses control complement

A
  • produce homologues of complement control proteins
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10
Q

what are the characteristics of a latent infection

A

virus will infect a non replicating cell OR the viral genome will replicate in conjunction with the host DNA replication so the cell cycle is not disrupted
the viral genome persists in cell
expression of productive cycle viral genes is absent or inefficient
immune detection of the cell with the latent genome is reduced or eliminated

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11
Q

what type of infection is HSV

A

latent

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12
Q

what type of infection is EBV

A

latent

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13
Q

what type of infection is Hep. B and C

what do they lead to

A

chronic - viral persistance

immune exhaustion by producing viral proteins constantly

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14
Q

what type of infection is HPV?

A

cytopathic but in a inaccessible site - persistance

virus in top layers of skin where there is not a robust immune response

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15
Q

what is an example of a acute infection with very late complications

A

measles - SSPE
- initial infection with measles
- CNS becomes infected
- the immune system selects for a variant of measles that doesn’t express viral glycoprotein therefore it can no longer bud out of the cell
the genome will spread gradually from neuron to neuron and leads to encephalitis

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16
Q

what viruses use antigenic variation

A

hiv and influenza

17
Q

how does antigenic variation allow virus to escape immune system

A
  • allows virus to escape Ab’s
  • change in epitopes allow the virus to escape neutralisation by the immune system
    occurs spontaneously though the rdrp
18
Q

how are the ways that viruses can be undetected by T-cells

A
  • drift in t-cell epitopes:
    Selective pressure of T cells can lead to escape variants that avoid recognition due to mutations that:
  • Change the anchor residues of epitope so it no longer binds well to MHC
  • Change flanking amino acids so epitope is no longer processed from intact antigen
  • Change the epitope in TCR contact residues so it can be processed and presented but existing T cells can no longer recognise the presented peptide
19
Q

how can HCV escape recognition by t-cells?

A

In chronic HCV patients, variants have been created with mutations in TCR contact residues - due to these mutations there are no T-cells with TCRs capable of interaction with the anitgens (exploitation of ‘hole in the repertoire’).

20
Q

how does vaccinia virus inhibit T-cell priming by DCs

A
  • Vaccinia virus and HCV block cytokine induced maturation of DC
  • Vaccinia virus encodes a homolog of the cytoplasmic tail of TLR4 that inhibits signal transduction to initiate maturation of the DC (so signalling downstream cannot occur)
21
Q

How does HIV avoid detection from CD8 cells

A
  • HIV has antigenic variation in CTL epitope
  • HIV Nef protein induces the endocytosis of Class I molecule where it gets degraded
  • HIV decreases MHC1 gene expression
22
Q

what does HSV ICP47 do

A

HSV protein ICP47 binds to cytosolic side of TAP transporter and prevents peptide translocation into the lumen of the ER
avoids detection from CD8

23
Q

what does CMV protein US6 do

A
  • CMV protein US6 binds to TAP transporter on luminal side and prevents peptide translocation into the cytosol
    avoids detection from CD8
24
Q

what does adenovirus E3 do

A
  • Adenovirus protein E3 binds MHC peptide complex and retains it in ER and inhibits recruitment of TAP to the peptide loading complex
25
Q

what does EBNA-1 do in latently infected b-cells do

A
  • EBNA-1 in latently infected B cells evades proteasome degradation therefore cannot be presented on MHC
26
Q

how much MHC is it beleived that viruses display

A

50%

enough that NKs are not activated

27
Q

what virus is good at evading NK cell detection

how

A

CMV
- Murine CMV encodes a protein (m152) which retains NKG2D ligands in the ER (you don’t get expression of the activating ligand on the for NKG2D)

  • Human CMV encodes an MHC1 like molecule (UL18) which is expressed on surface of infected cell and delivers a negative signal to NK cell, but cannot present peptides to CD8 T cells (cannot be recognised)
  • Human CMV upregulates the expression of the cellular non-classical HLA-E which is a class I molecule that only binds and presents the signal peptides of other MHC molecules - NK cells see this as normal
28
Q

what virus produces a soluble cytokine receptor homologue

what is it and what does it do

A

Poxvirus
(vaccinia, myxoma)
- encode homologues of IFN-a/bR , IFN-gR, TNF-aR and IL-1bR that bind the cellular cytokines and inhibit their function (they make receptors that bind to cytokines to mop them up)

  • In some cases the homologues can bind to monomeric receptors and inhibit formation of the active multimer
  • Mutant viruses lacking these receptor homologues are greatly reduced in virulence
29
Q

what does EBV encode to redirect the t-cell response

A
  • EBV encodes an viral IL-10 homolog that suppresses a Th1 response (therefore reducing CTLs)
30
Q

what does crmA protein do and what virus produces it

A

Poxviruses encode crmA protein which inhibits the cleavage of IL-1b precursor to mature secreted form so virus-infected cell does not release IL-1b so inflammatory response is reduced

31
Q

how does adenovirus interfere with intracellular cytokine function

A

Adenovirus encoded proteins interfere with pathway of TNF-a mediated killing of the cell

32
Q

what proteins control apoptosis and how does it start apoptosis

A
  • Regulatory proteins in the BCL-2 family control this process which can proceed by either
    (i) permeabilization of the mitochondria or
    (ii) direct signalling through TNF or FAS
33
Q

why do viruses want to avoid apoptosis

A

Viruses require an intact and functional cell in which to replicate and apoptosis is a means of anti-viral defence

34
Q

what are the two pathways of apoptosis

A
  • Extrinsic pathway: exogenous TNFa binding to a receptor on the cell surface will cause intracellular signalling and lead to cell death via apoptosis
  • Intrinsic pathway: cytochrome C release from the mitochondria will leak out from the mitochondria from viral damage and induce apoptosis
35
Q

what virus induces apoptosis

why

A

norovirus will induce apoptosis of the cell to be released

36
Q

what is autophagy? what is it used for?

A

Autophagy process by which bulk cytoplasm is enveloped inside a double-membraned vesicle (an autophagosome) and shuttled to lysosomes for degradation (this is a normal daily function)

  • It has Antiviral functions:
    (i) targeting of viral components or virions for lysosomal degradation (xenophagy)
    (ii) role in the initiation of innate and adaptive immune responses
37
Q

how does Poxvirus control complement?

A

vaccinia has a protein that binds C3b and C4b

38
Q

how does autophagy have a role in the activation of the immune response

A

if TLR7 is activated in the endosome - autophagy will be promoted and cross presentation of virus can occur

39
Q

how do viruses evade autophagy

A

some viruses replicate on the autophagosome membrane
- they sequester the membranes for replication
they cannot be detected

Virology 11-20 (8 decks)

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