Immune evasion by viruses Flashcards
Antiviral Immunity - how can it be split?
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)
which viruses have to deal with the non-specific mechanisms our body has in place?
All viruses have to deal with this!
which viruses have to deal with the specific mechanisms our body has in place?
only slow acute or chronically infecting viruses
most imp non-specific mechanism?
Interferon is the most important, all viruses will have to deal with it, any virus that cant doesn’t make it
explain how viral evasion of the IFN system occurs
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
which viruses are severely attenuated? name some examples
those that can’t block IFN system
- Influenza ΔNS1 strains are severely attenuated (3 logs) and can be used as the basis for vaccine strains
- BVDVΔNpro strain is severely attenuated (3 logs) and can be used as a vaccine strain
- 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
is IFN production simple?
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
Paramyxovirus targets in IFN production
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
Other virus targets in IFN production
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
The JAK/STAT signalling pathway
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
how do viruses professional evade the IFN system?
By encoding genes that inhibit production of IFN or its signalling
Evasion of Inflammation
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
Intrinsic defences – “the hostile cell”
Apoptosis RNA silencing Epigenetic silencing Autophagy/Xenophagy Restriction factors/Intrinsic Immunity
Apoptosis
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
Mechanisms of Apoptosis
see diagram
Caspases that chop up the cell, DNA and various other proteins
how does adenovirus inhibit apoptosis?
The E1b protein of adenoviruses has the ability to stop apoptosis
-an anti-apoptotic adenoviral Bcl-2 homologue
how does KSHV inhibit apoptosis?
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
Restriction Factors?
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
how does HIV combat the host restriction factors?
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.
NK cells and Herpesvirus infections
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
How do NK cells work?
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
how does CMV affect HK function?
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
Inhibition of NK function by mCMV –
co-evolution of virus and host
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
why doesn’t complement attack self?
because you have complement regulatory proteins on the surface to inhibit it
Viruses like HHV and vaccinia have complement protein homologs
