What is a key difference between internal virus proteins and surface antigens - and how does it make it a better target for immunity
- Internal viral proteins vary less so…..
- This makes it a better target for cellular immunity
Describe the process of presentation of viral peptides on MHC Class I
- Viral peptides are chopped up by the proteasome
- These peptides are then fed through the TAP protein into the endoplasmic reticulum
- In the endoplasmic reticulum, it will be transferred from TAP to Tapasin
- Tapasin loads the viral peptides onto the peptide groove on an MHC class I molecule whilst they are still in the ER
- The loaded MHC I : viral peptide complex will then move to the cell surface where T-cells can recognise the antigen
State three viruses (and the proteins involved) that evade antigen loading onto TAP and describe the mechanisms behind how they do this
- EBV – EBNA1 – this cannot be chopped up by the proteasome
- HSV – ICP47 – blocks access of the peptides to the TAP protein
- CMV – US6 – blocks ATP binding to TAP, preventing translocation
State two viruses (and the proteins involved) that modulate tapasin function and prevent MHC transport
- NOTE: tapasin is involved in loading MHC molecules
- Adenovirus - E3-19K – prevents recruitment of TAP to tapasin and retains MHC in the ER
- CMV – US3 – binds to tapasin and prevents loading of peptides onto MHC I
State one virus (and the protein involved) that interferes with MHC presentation at the cell surface
- KSHV (Kaposi Sarcoma Herpes Virus) – kK3: induces polyubiquitination (coats the loaded MHC I with ubiquitin protein) and internalisation of MHC I to prevent it presenting the viral peptide to the T-cell
- Once internalised, the loaded MHC I is transferred to an endosome and then into a lysosome where it is degraded
What do NK cells recognise on the cell surface that triggers killing of cells?
- Missing self – lack of MHC on the cell membrane
- NK cells recognise this and destroy cells that do not present the MHC I
1) Why might the missing-self process be a problem for viruses?
2) Give a way in which viruses might evade this missing-self mechanism and give a named example (of the virus and the product)
1)
- Viruses tend to develop methods to prevent or interfere with MHC I presentation in order to avoid bringing about the adaptive immunity response
- Therefore there is often poor or lack of MHC I presentation on infected cells
- This lack of MHC I presentation is the missing-self - this brings about NK-mediated killing of these infected cells
2)
- Viruses encode MHC analogues
- Eg. CMV synthesises gp UL40
- This virally encoded MHC is useless but it fools the NK cells into thinking the infected cell is functioning normally and still presenting an MHC
- Or some viruses upregulate MHC
Describe the way in which you can manipulate the way CMV interacts with infected cells to develop a treatment procedure for transplant patients
- CMV produces UL138 proteins that lead to loss of MRP-1
- MRP-1 usually transports toxic substances out of host cells
- So you can treat cells from donor with vincristine (not too much or it would be too toxic to even uninfected cells)
- So vincristine accumulates in infected cells and therefore selectively targets and kills infected cells
Which cells does HIV target?
- CD4+ T cells
Which cells does Ebola kill?
- Dendritic cells
- Macrophages
- T-cells (by the bystander response)
What is antigenic drift, and give a virus that phenomenon is common in?
- Continued rapid evolution driven by antigenic pressure from the host - this is a more subtle change in the antigen structure to evade host immunity
- This is common in influenza
What is antigenic shift and in which viruses is this common?
- Antigenic shift = introduction of new viral subtypes from an animal source
- There is a much larger change is the antigenic structure than with antigenic drift
- This is common in influenza
How else (aside from antigenic drift and shift) can viruses cause regular infections without changing their antigen profile - give an example virus ?
- They can have several genetically stable serotypes that co-circulate
- E.g. rhinovirus has more than 120 antigenically distinct serotypes
What are HIV quasispecies?
- Massively diverse appearance of HIV genetic diversity due to constant genetic mutation
How many serotypes of influenza are there?
- 4
How many serotypes of poliovirus are there and what type of vaccine was produced for polio?
- 3 – trivalent vaccine
- NOTE: one of the serotypes has been eradicated now
1) What is sterilising immunity?
2) When does sterilising immunity fail?
1)
- Sterilising immunity = when antibodies coat viruses before it can latch to host receptors - therefore preventing secondary infection
2)
- Sterilising immunity fails when the antigen changes its epitope structure - so the antigen is longer recognised and coated
- So the virus can interact with host cell and cause infection
1) Describe the principle behind influenza vaccines - what we are trying to achieve
2) Describe how influenza viruses become useless
3) What is the new proposition for how to develop flu jabs to counteract this problem?
1)
- We are trying to develop sterilising immunity - where the antibodies coat the antigens to prevent them from interacting with target cells receptors
2)
- Due to antigenic drift, the epitope of the antigen is unrecognisable by antibodies developed in response to the serotype within the vaccine
3)
- Rather than develop to target antigens on the head of pathogens where there is lots of antigenic variation…
- Develop for antigens on the stem, where there are more conserved sequences (less antigenic variation) so we can be less worried about antigenic drift
What happens in Dengue Fever, what is seen in the bloods and what is caused?
- Leakage of plasma from capillaries leads to:
- Increased haematocrit
- Increased red cell count
- Decrease in serum protein
- Tendency to severe bruising and bleeding
What is the treatment for DHF?
- IV fluids
How many serotypes of dengue are there?
- 4
1) Explain the significance of the presence of multiple serotypes of dengue with regards to the pathogenesis of DHF - cytokine storm
2) Therefore what consideration is made in developing vaccines for Dengue Virus?
1)
- Infection with one serotype will cause antibody production
- Upon subsequent exposure to a different serotype of dengue virus, the antibody generated against the previous serotype will bind to but NOT neutralise this
- This can lead to ANTIGEN DEPENDENT ENHANCEMENT (ADE)
- This is where monocytes recognise the fc receptors on the antibodies so internalises it, taking the dengue virus along with it inside the monocytes
- Dengue virus replicates within the monocyte
- The monocytes secretes loads of IFN in response - leading to the cytokine storm in Dengue Haemorrhagic Fever
2)
- You must vaccinate against all 4 Dengue Virus serotypes simultaneously to avoid inducing DHF
How is Dengue Haemorrhagic Fever brought about - describe the pathophysiological processes and what it is?
- Primary infection with a certain serotype of Dengue Virus
- An antibody is produced against this
- Upon secondary infection with a different serotype, this antibody will be useless
- It will just bind the new serotype but not neutralise it - causing ADE (antibody-dependent enhancement)
- I.e. these antibodies become harmful as they help the virus as they give it a new entry route into immune cells via their Fc receptors e.g. into monocytes
- Therefore viral replication can occur in these immune cells
- The immune cells e.g. monocytes produces lots of cytokines like IFNs - leading to a cytokine storm
1) What is the main function of Gp120 on HIV?
2) Describe the ways in which Gp120 on HIV can be useful in evading antibodies
1)
- Gp120 binds CD4 via CD4 binding site
- From here HIV can enter the CD4 positive TH cells
2)
- Gp120 is few and far between - therefore its resistant to antibody cross-linking
- HIV extensively glycosylates Gp120 to coat and mask the epitopes at the CD4 binding site on the Gp120 against interacting with the antibodies
What can viruses do to glycoprotein antigens that hinder antibody access to the antigens?
- Heavily glycosylate the antigens
What are bNabs and why are they useful in treating HIV?
- bNab = broadly neutralising antibodies
- These antibodies can cross-react with many HIV strains which is useful since HIV has many quasispecies so this is very useful in HIV control
What are bNabs, and what do they select for?
- bNab = broadly neutralising antibodies
- Initially they are useful in controlling viral infection, but then since they are so broad in their specificity…
- They select for escape mutants
What does Ebola viruse have a high content of that makes them appear like apoptotic bodies?
- Phosphatidyl serine lipids
What is the benefit to Ebola virus of appearing like apoptotic bodies?
- They are rapidly taken up by macropinocytosis and, hence, taken away from antibody surveillance
How does the structure of Ebola affect antibody access to antigens?
- Ebola has a long filamentous shape with lots of folds
- The folds may make the glycoproteins inaccessible to antibody
Name two factors produced by Ebola that allow it to evade detection by the innate immune system
- VP35
- VP24
What important factor does Ebola encode that also helps deal with the antibody response?
- Soluble glycoprotein – this acts as an antibody decoy and it is immunosuppressive (inhibits neutrophils)
- I.e. it binds the antibodies whilst the Ebola goes off scot-free
- NOTE: GP2 and retrovirus glycoproteins also have an immunosuppressive peptide
Summarise the ways in which Ebola can evade antibodies and also immunosuppress
- Glycoprotein antigens are heavily glycosylated - this inhibits antibody access
- Also, Ebola has a long filamentous shape with lots of folds - this makes the glycoproteins inaccessible to antibody
- Ebola secretes soluble glycoproteins that act as a decoy for antibodies - i.e. the antibodies bind them and occupy them instead of the actual Ebola
- Ebola also secretes VP35 and VP24 which inhibit the IFN response
- Ebola pretends to be an apoptotic body so it can be rapidly taken up by pinocytosis and removed from the extracellular environment where it would be vulnerable to antibodies
- GP2 and retrovirus glycoproteins have an immunosuppressive peptides
1) How does Measles infect cells?
2) Why does Measles result in immunosupression?
1)
- Via SLAM proteins (on CD150 positive cells)
2)
- By infecting CD150 positive cells
- Memory lymphocytes are CD150 positive - so by infecting these and lysing them, it suppresses the immunological memory that it allows so you are causing immunosuppression
Why did the measles vaccine have a much larger effect on childhood mortality than expected?
- Measles can infect memory lymphocytes (these are SLAM positive) and erase immunological memory
- So a measles virus infection can result in decrease in immunological memory that leads to morbidity and mortality from other diseases
- Therefore vaccination against measles protects against both measles infection and against other diseases that could result as a result of the immunocompromised state that measles virus would have otherwise brought about
1) What are the 2 types of vaccines available for polio?
2) How many serotypes of Polio virus are there - therefore what particular formulation of vaccine is there?
1)
- LAV (live attenuated virus) e.g. Sabin
- Dead vaccine
2)
- 3 poliovirus serotypes → trivalent poliovirus vaccine
Give 3 ways in which Hep C evades the immune system
- Its E2 protein varies lots so antibodies can only bind a small fraction of the viral quasispecies
- NS4 / 4A protease cleaves MAVS and prevents IFN activation
- A genetic polymorphism in IL-28b (IFN lambda receptors) results in non-responsiveness to IFN