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BI405 (ii) > Anti-viral immune response (ii) > Flashcards

Anti-viral immune response (ii) Flashcards

1
Q

What does a successful virus co-exist with?

A

A successful virus co
exists with the host (obligate
parasite).

Viruses are highly evolved and target key aspects of the
host anti-viral response.

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2
Q

What type of immune responses do viruses target?

A

Viruses target
both innate and adaptive immune responses.

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3
Q

Evasion

A

can be either passive (avoiding detection) or active inhibition

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4
Q

Subversion

A

utilising a host protein for the benefit of the virus (chemokine system, transcription factors, polymerases, proteases….). The host protein helps the virus to replicate.

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5
Q

Name the Group I (dsDNA) Viruses with well studied immune evasive strategies.

A

*Adenoviruses
*Herpesviruses:
a Herpes Simplex Virus (HSV)
bCytomegalovirus (CMV)
γ Epstein Barr Virus (EBV)

*Poxviruses:
vaccinia virus, cowpox
ectromelia virus, variola virus
molluscum contagiosum virus

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6
Q

Group IV (ss(+)RNA)

A

Flaviviruses (Hepatitis C)

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7
Q

Group V (ss(-)RNA)

A

Orthomyxoviruses (Influenza)

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8
Q

Group VI (RNA RT)

A

Retroviruses (HIV)

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9
Q

What do viruses try to do to Interferon I

A

Viruses try to block induction of type I interferons and/or their action.

Viral evasion strategies target type I
IFN induction and signalling at
different levels and by different
mechanisms.

IFNs are key target of viral evasion strategies.

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10
Q

Name the two examples of viruses that evade PRR signalling

A

1.The Poxvirus proteins A46 and A52
2. The Hepatitis C Virus protease NS3/4a

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11
Q

Poxvirus protein A46

A

Discovery provided early evidence for the involvement of TLRs in the anti-viral response.

A46 contains a TIR domain
and prevents interaction
between TLRs and TIR
adaptor molecules.

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12
Q

Poxvirus protein A52

A

A52 blocks NF k B activation and pro-inflammatory
cytokine induction by targeting Irak2.

Through subverting TRAF6 function, A52 enhances
p38 MAP kinase activation and production of
the anti-inflammatory cytokine IL 10.

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13
Q

The Hepatitis C virus protease NS3/4a

A

HCV protease NS3/4a is required for processing of the viral polypeptide, i.e. the production of viral proteins. In an additional immune evasion function it cleaves
TRIF and prevents TLR3 and TLR4 signalling to IRF3 activation (also IPS 1 cleavage, see slide 38).

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14
Q

What are the key strategies for viral evasion of PRR signalling (RIG-like helicases)?

A

1.Mask the substrate: avoid recognition
2.Target the receptors and block
binding/activation: mda 5 and RIG I
3.cleavage/Inhibition of key downstream
signalling components

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15
Q

How do viruses (viral evasion of RLH signalling) avoid recognition?

A

*viruses mimic host RNA (mask or remove 5’ppp end)

*dsRNA-binding proteins (shielding dsRNA from recognitoin by PRRs)

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16
Q

How do viruses mimic host RNA ?

A

*cap viral mRNAs with 7
methyl guanosine cap (same as host
mRNA), using host machinery or virally encoded capping enzymes
(poxviruses, rotaviruses), ‘cap snatching’

*Processing of 5’ppp to 5’p by a viral phosphatase (Borna disease
virus)

*protect 5’ end by covalently linked protein VPg (Ebola Virus)

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17
Q

name the dsRNA-binding proteins (shielding dsRNA from recognition by PRRs)

A

*VACV E3 protein
*Ebola Virus protein VP35
*HIV Tat
*Influenza virus NS-1

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18
Q

Explain cleavage of MAVS/IPS-1

A

Hepatitis C virus protease NS3/4a cleaves TRIF and IPS
1 and thereby
blocks both TLR3/4 signalling (slide 32) and RIG like helicase signalling .

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19
Q

What are NS3/4a inhibitors used for?

A

NS3/4a inhibitors are used therapeutically for HCV infection

20
Q

How does HIV-1 remove DNA?

A

HIV 1 uses TREX1, the
most abundant 3′ 5′
DNase in cells, to
remove extra copies of
its retro transcribed
DNA.

21
Q

STING as a major target

A

-deubiquitination
-Cleavage (DENV
NS2B NS3)
-Inhibition or
sequestration

22
Q

How does the VACV protein K7 inhibit IRF3/7 activation?

A

VACV protein K7 interacts with DDX3, this led to the
discovery of a novel role for DDX3 in IRF3 activation

23
Q

Direct tareting of IRF3 and IRF7

A

Inactive viral IRF3 mimetics that compete with cellular
IRF3 (Paramyxovirus V proteins, Herpesviruses),
sequestering of IRF3 (HSV ICP0), degradation
of IRF3 (HIV Vpr , Rotavirus NP1)

24
Q

Examples :To inhibit IFN signalling

A

Examples:

*Poxvirus soluble IFNa/b receptor (B18R)

*Adenovirus E1A binds to Stat1, downregulates Stat1 and IRF9 levels.

*Paramyxovirus V proteins can lead to Stat1 and Stat2 degradation

*Sendai virus C proteins bind to Stat1

25
Q

What do viral evasion proteins target?

A

-key proteins in PRR signalling pathways leading to type I IFN production/induction.

-key proteins in IFN signalling (Stat1/2)

-Or mask viral RNA (hide 5’ppp, dsRNA)

26
Q

What is Nf-kB activation important for?

A

NF-kB activation (via PRRs) is important for anti viral and pro inflammatory gene
transcription.

27
Q

What do some viruses use NFkB for?

A

–Transactivate viral genes (HIV…)
–Prolong survival of infected cell
–Transform cells

28
Q

Describe Early Stage Infection of African Swine Fever Virus +Nf-kb

A

*Early Stage Infection delays the innate immune response.

*A238L is the early gene.

*Ik B homologue,
sequesters NF k B in
cytoplasm, inhibits
NF kB activation.

*Evasion

29
Q

Late Stage Infection of African Swine Fever Virus +NKF-kB

A

*Late Stage Infection

*Avoid Apoptosis, ensure cell survival

*A224L - late gene

*Activates Nf-kB, inhibits caspases

*Subversion

30
Q

What are the common strategies for viral manipulation of cytokines?

A
  1. Block pro-inflammatory cytokines and chemokines. (e.g. decoy receptors, cytokine binding proteins, antagonistic cytokines, block NF kB activation)
  2. Enhance production of anti inflammatory cytokines
    (IL 10)
31
Q

Viral soluble cytokine & chemokine “decoy” receptors

A

*Soluble cytokine and chemokine receptors have no transmembrane
region.

*They sequester cytokines/chemokines in the extracellular space and prevent them from binding to their signalling active
cytokine/chemokine receptors on cells.

*They therefore act as ‘decoy’ receptors, neutralise the cytokine, and inhibit its effect.

32
Q

CD8+ cytotoxic T cells

A

-Important cells for killing virus
infected cells

-Viral Peptide presented on MHC class I (through endogenous antigen
processing pathway) by APC activates cognate CD8+ T cell.

-Activated CD8+ T cell recognises viral peptide/MHC I complex on infected
cells and initiates killing.

33
Q

VIRPS

A

Viral proteins Interfering with antigen Presentation

34
Q

Function VIRPS

A

*Different VIPR proteins block different steps in MHC I antigen presentation pathway.

*Prevents CD8+ T cell activation and effector function

*reduce MHC class I expression on surface of
the cells (viral and cellular antigens cannot be
presented)

*prevent viral antigen from entering the MHC class I presentation pathway

35
Q

Example of how VIPRs prevent viral antigen from entering MHC I presentation pathway.

A

Epstein Barr Virus protein EBNA1:

*produced in latently infected B cells

*No EBNA1 peptides detectable on MHC class I of these B cells

*No ubiquitination or proteasomal degradation of EBNA1

*Mediated by a Gly Ala repeat sequence

36
Q

VIPRs Prevent MHC class I expression and antigen presentation.

Example 1: Block Tap Function (no peptide transport into ER)

A

Herpes Simplex Virus (HSV)
ICP47 protein binds to TAP with high
affinity and prevents peptide binding on the cytosolic side.

37
Q

VIPRs Prevent MHC class I expression and antigen presentation.

Example 2: Block MHC I secretion

A

Adenovirus E19 protein has an ER retention motif, binds to MHC class I a chain in the ER lumen, prevents its shuttling.

38
Q

VIPRs Prevent MHC class I expression and antigen presentation.

Example 3: Shuttle MHC I back to cytosol for degradation

A

hCMV US2/US11 proteins form a complex with MHC class I, lead to its glygosylation, retrograde translocation into the cytosol and proteasomal degradation.

39
Q

VIPRs Prevent MHC class I expression and antigen presentation.

Example 4: Remove MHC I from the cell surface

A

HIV 1 nef protein promotes endocytosis of MHC class I complexes

40
Q

Name the types of antigenic variation

A

Antigenic drift and antigenic shift

41
Q

Antigenic drift

A

(point mutations in viral
RNA viruses have high mutation rates, a particular viral antigen can therefore change within the course of an infection. This generates escape mutants.

42
Q

Antigenic shift

A

(RNA segments are exchanged between
viral strains in a secondary host). Leads to major changes in viral epitopes, surface proteins, can lead to severe global pandemics.

43
Q

Natural Killer (NK) cells

A

-Innate immune cells

-kill by releasing cytotoxic granules filled with perforin
and granzymes (similar to CD8+ cells)

-their killing activity can be enhanced by cytokines, such
as IFN a , IL 12 and IL 18.

-in response to IL
12 and IL 18, they also produce IFN g
(similar to Th1

-have germline encoded invariant receptors

-are very important in the early phase of a
viral infection (kill infected cells) and in anti tumour responses

44
Q

altered self (NK cells)

A

NK cells recognise changes in cellsurface glycoprotein composition induced by metabolic stress

45
Q

missing self

A

NK cells react to lack of MHC class I molecule expression

46
Q

Viral NK cell evasion strategies

A

-Trigger expression of ligands for inhibitory NK cell receptors

-downregulate expression of ligands for activating receptors

-produce cytokine antagonists

-infect and kill NK cells

BI405 (ii) (4 decks)

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