Immune evasion by viruses

Question 1

Antiviral Immunity - how can it be split?

Answer 1

non-specific and specific mechanisms:

Non-specific mechanisms
Phagocytosis
Inflammatory Response
Cytokines and Interferon
Intrinsic Defences
NK cells 
Natural IgM 
Complement

Specific Mechanisms
Humoral (antibodies)
Cell-mediated (cytotoxic T cells)

Question 2

which viruses have to deal with the non-specific mechanisms our body has in place?

Answer 2

All viruses have to deal with this!

Question 3

which viruses have to deal with the specific mechanisms our body has in place?

Answer 3

only slow acute or chronically infecting viruses

Question 4

most imp non-specific mechanism?

Answer 4

Interferon is the most important, all viruses will have to deal with it, any virus that cant doesn’t make it

Question 5

explain how viral evasion of the IFN system occurs

Answer 5

In order to replicate in the face of a powerful innate immune response, viruses must make a major effort to evade the interferon system

You have a primary infected cell, no adaptive component to this. Virally infected cell will secrete IFN, which will bind to receptors on neighbouring uninfected cells to trigger the anti-viral state.

All viruses encode antagonists to the interferon system

Question 6

which viruses are severely attenuated? name some examples

Answer 6

those that can’t block IFN system

1. Influenza ΔNS1 strains are severely attenuated (3 logs) and can be used as the basis for vaccine strains
2. BVDVΔNpro strain is severely attenuated (3 logs) and can be used as a vaccine strain
3. PIV5VΔC is severely attenuated (can’t be grown in IFN-competent cells) and can be used as an experimental vaccine

For viruses like herpes that have over 200 genes, they may put aside 20 genes for disabling the IFN system

If you know which genes are the disabling ones, you can make a vacccine using those weak strains

Question 7

is IFN production simple?

Answer 7

no, there are many steps biochemical steps leading to IFN production

Viral antagonists have no favorite places to block, block all over the place doesn’t matter how

Question 8

Paramyxovirus targets in IFN production

Answer 8

PIV5 make a protein called V, it binds to the PRR stopping them from seeing PAMPs

Some stop the transcription factors in the nucleus from binding DNA

PIV5 can target STAT1 for proteolytic degradation -> no innate immune response so cant block viral infection

Many paramyxoviruses also block IFN Jak/Stat signalling

Question 9

Other virus targets in IFN production

Answer 9

Different strains of influenza, their NS1 antagonise IFN in different ways

H1N1 binds to RIG-I

H3N2 its NS1 operates on postranscriptional processing stopping it from properly capped and polyadenylated

Question 10

The JAK/STAT signalling pathway

Answer 10

IFN binds to receptor -> dimerisation of the receptor subunits

The 2 tyrosine kinases (JAKs), get recruited onto the cytoplasmic tail of this receptors

Then phosphorylate STAT1 and STAT2 to form a heterodimer which translocates into the nucleus
Bind to genes that turn on the antiviral response

Question 11

how do viruses professional evade the IFN system?

Answer 11

By encoding genes that inhibit production of IFN or its signalling

Question 12

Evasion of Inflammation

Answer 12

General block to inflammatory cytokine production

Direct inhibition of caspase-1(e.g. Vaccinia B13R)

Synthesis of scavenger receptors (e.g. Vaccinia vIL-1βR)

Blocking of inflammasome assembly (Measles V, Poxvirus M13L-PYD, KSHV Orf63

NS1 inhibits RIG-I inflammasome

Vaccinia also makes a soluble IL-1B receptor to inactivate all the IL-1 at the site of inflammation

Question 13

Intrinsic defences – “the hostile cell”

Answer 13

Apoptosis
RNA silencing
Epigenetic silencing
Autophagy/Xenophagy
Restriction factors/Intrinsic Immunity

Question 14

Apoptosis

Answer 14

Viruses activate apoptosis, often by producing dsRNA

Apoptosis is bad for the virus because it prevents completion of life cycle and triggers surface signals for clearance by macrophages

Many viruses specifically block apoptosis

Question 15

Mechanisms of Apoptosis

Answer 15

see diagram

Caspases that chop up the cell, DNA and various other proteins

Question 16

how does adenovirus inhibit apoptosis?

Answer 16

The E1b protein of adenoviruses has the ability to stop apoptosis
-an anti-apoptotic adenoviral Bcl-2 homologue

Question 17

how does KSHV inhibit apoptosis?

Answer 17

KSHV Bcl-2 possesses Bcl-2 homology (BH) 1 and BH2 domains characteristic of this family of proteins, allowing the viral protein to tightly bind proapoptotic Bak and Bax peptides, and thereby inhibit apoptosis

Question 18

Restriction Factors?

Answer 18

Particularly active against retroviruses:

APOBEC3G

• Highly potent ssDNA cytidine deaminase
• take out DNA from the RNA-DNA reverse transcriptase

TRIM5α

• Targets incoming capsids to proteasomes; very species-specific
• targets HIV capsids to proteosomal degradation

Tetherin
- Blocks budding by enveloped viruses

Question 19

how does HIV combat the host restriction factors?

Answer 19

HIV makes tat and rev
HIV-1 makes protein called vpu but others don’t
HIV-2 makes vpx which others don’t
We now know that these proteins antagonise restriction factors

HIV comes in, TRIM5 tries to target capsid for degradation but this fails. Then RNA gets copied to DNA and that heteroduplex is targeted by APOBEC which deamidades the cytadine – this is antagonised by vif.

Question 20

NK cells and Herpesvirus infections

Answer 20

Mice depleted of NK cells have significantly higher (up to 500-fold) titers of MCMV, MHV, or vaccinia virus in their livers and spleens as compared to control mice.

A major function of NK cells against MCMV and MHV is IFN-γ secretion.

Vaccinia infection controlled by lytic function of NK cells

Question 21

How do NK cells work?

Answer 21

How NK cells work

In an uninfected cell, self peptide presented on MHC-I to an inhibitory receptor. You will present the peptide of the MHC I through the groove of HLA-E to another inhibitory receptor. Little ligand presentation to activating receptors

In an infected cell you have down regulation of MHC I and HLA-E so you have nothing to engage the inhibitory receptors. Activating ligands increase and engage the activating receptors – activation of NK cells

Question 22

how does CMV affect HK function?

Answer 22

Inhibition of NK function

CMV – encode a lot of proteins that are involved in downregulating MHC-I -> no adaptive immune response. Usually, this would lead to increase in activating ligands and receptors to activate NK

But CMV has genes that prevents activating ligands
UL142 – HLA-decoy to engage NK inhibitory receptor to look like it is a HLA-E. UL40 is a peptide the peptide binds to the groove of HLA-E.
UL-16 – downregulate the production of activating receptor. So this also prevents the presentation of viral peptides to CTL, but also prevents NK cell activation

Question 23

Inhibition of NK function by mCMV –

co-evolution of virus and host

Answer 23

murine CMV - uses decoy receptor m157 to present to Ly49I leading to NK inhibition

breed mice to be resistant, the mouse takes Ly49I and recombined it with another NK cell receptor to give a new allele called Ly49H -> this has the same binding site to bind m157, but when engaged rather than acting in an inhibitory fashion, it activates the NK cell -> activation phenotype

Question 24

why doesn’t complement attack self?

Answer 24

because you have complement regulatory proteins on the surface to inhibit it

Viruses like HHV and vaccinia have complement protein homologs

Question 25

Evasion of Complement

Answer 25

Incorporation of complement control proteins into envelope

Passive

Active:
Vaccinia C3L gene product = VCP. Complement control protein binds to and inactivates C3b and C4b

Vaccinia B5R gene product – recruits host complement control proteins into envelope

KSHV(HHV-8)-encoded KCP; incorporated into the virion; enhances the decay of classical C3 convertase and induces the degradation of activated complement factors C4b and C3b by a serine proteinase, factor I.

Question 26

Active mechanisms of evading adaptive immunity

Answer 26

Viral IgG Fc receptors, binding of IgG and inhibition of Fc-dependent immune activation

These are secreted receptors to scavange the IgG in that local site

• Varicella Zoster (HHV3)
• CMV (HHV5)

Question 27

Viral anticytokine and antichemokine strategies

Answer 27

Homologues of cellular cytokines that influence the development of the immune response.

Homologues of cellular cytokine receptors, e.g. TNF, IFN, IL-1, IL-18

Binds chemokines (bind CKs or CK receptors) 
Inhibit intracellular signalling pathway,  e.g. induction of chemokines/cytokines (via NF-κB activation) or IFN response.

Block cytokine secretion

Question 28

Latency and immune evasion

Answer 28

When viruses enter into a latent state they dramatically reduce the number of genes they express (e.g. EBV drops from over 100 genes to between 5 and 8).

This makes them much less immunogenic

Question 29

examples of persistent infections?

Answer 29

HIV and Hep c

Question 30

how does antigenic variation affect HIV?

Answer 30

it allows HIV to escape neutralising antibodies

Question 31

Antigenic variation in acute versus chronic infections

Answer 31

HCV and HIV chronically infect the host and antigenic variation is a necessary part of this

Acutely infectious viruses generate antigenic variants. These are not necessary for the course of infection and their generation is not a survival strategy for an ongoing infection

Question 32

Pox viruses and immune evasion

Answer 32

VGF vaccinia V growth factor is homologue of epidermal growth factor (EGF) - binds to EGF receptor stimulating anchorage independent growth.
VGF 22-27% homology to vascular endothelial growth factor

E3L homologus to N terminus of PKR - the part that binds dsRNA