Viral Evasion of the Host Immune Response Flashcards
What is a key difference between internal virus proteins and surface antigens?
Internal viral proteins vary less
Viruses are intracellular pathogens so their proteins are easy targets for
processing and presentation by MHC
Cellular immunity clears viral infection but is short-lived
Internal viral proteins can be targets for cellular immunity - as they are
intracellular, they tend to vary LESS than the surface antigens
Viruses that persist must evade 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 loaded onto an MHC class I molecule and it will then move to the cell surface where T cells can recognise the antigen.
Foreign peptides inside the cell (e.g. viral peptides) will be chopped up into smaller peptides inside the proteasome
They then get fed in through the TAP protein into the endoplasmic reticulum where it gets loaded onto an MHC class I molecule
This loaded MHC then moves to the cell membrane where the viral peptide can be recognised by T cell receptors on the surface of cytotoxic T cells
The T cell can then kill the virus infected cell
Viruses that persist must be able to suppress this system
State three viruses (and the proteins involved) that evade antigen loading onto TAP.
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
RECAP: the proteasome chops up the viral peptides and loads them into the endoplasmic reticulum through TAP (transporting molecule)
EBV expresses a protein called EBNA1 that CANNOT be cut up into smaller peptides in the proteasome - so EBV can exist in the cell but its proteins are not processed
HSV encodes ICP47, which blocks access of the processed peptide to TAP
CMV encodes US6 which stops ATP binding to TAP, which is required for TAP to
be able to transport peptides across the membrane
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
CMV encodes US3, which binds to tapasin and prevents peptides being loaded onto MHC
Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the ER
State one virus (and the protein involved) that interferes with MHC presentation at the cell surface.
KSHV (Kaposi Sarcoma Herpes Virus) – kK3 – induces polyubiquitination and internalisation of MHC
Kaposi Sarcoma Herpes Virus (KSHV) kK3 protein induces polyubiquitination and internalisation of MHC
If MHC isn’t present on the cell surface then the virus peptides wont be presented to T cells
From the internalised endosome, MHC is passed on to lysosomes 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 is not healthy
How viruses avoid NK killing by the missing-self mechanism
Normal, healthy cells all display MHC on their cell membrane
Cells that do NOT display MHC are detected by NK cells and killed
This means that viruses that disrupt MHC presentation would end up being
killed by NK cells
To avoid this, viruses encode MHC analogues (e.g. CMV gp UL40) or upregulate
MHC
The virally encoded MHC is useless and does NOT trigger the immune response but it does fool the NK cells into thinking that the cells are normal
How do viruses evade this mechanism of NK-mediated killing infected cells?
Viruses encode MHC analogues (e.g. CMV gp UL40) – virally encoded MHC is useless but it fools the NK cells Upregulate MHC
Which cells does HIV target?
CD4+ T cells
HIV targets CD4+ T cells and depletes the ability to support an immune
response
Ebola virus infection also results in the destruction of target dendritic cells and
macrophages by direct infection and of T cells by a bystander response
Which cells does Ebola kill?
Dendritic cells Macrophages T cells (by the bystander response)
In what subset of the population does HMCV (human cytomegalovirus) cause disease?
Immunocompromised
What is the problem with HCMV with regards to bone marrow transplantation?
HCMV infects 60-90% of the population If HCMV is present in donated bone marrow, it could cause problems in the immunocompromised recipient
Explain how our knowledge about HCMV has allowed improved medical outcomes in bone marrow transplantation.
HCMV encodes UL138, which leads to loss of MRP-1 from the infected cell surface MRP-1 is a transporter of toxic drugs out of the cell Loss of MRP-1 leads to accumulation of certain molecules in the infected cell Vincristine is a toxic drug that accumulates in the infected cells and kills them So treating donated cells with vincristine before the transplant can eliminate CMV
What is antigenic drift?
Continued rapid evolution driven by antigenic pressure from the host
What is antigenic shift?
Introduction of new subtypes of the virus from an animal source NOTE: when they come from an animal source, the antigens don’t look like anything that humans have seen before
How else can viruses cause regular infections without changingtheir antigen profile?
They can have several genetically stable serotypes that co-circulate E.g. rhinovirus has more than 120 antigenically distinct serotypes
How many serotypes of influenza are there?
4
Influenza exists as FOUR different serotypes that are drifting year on year
WHO tries to predict which influenza serotype is most likely to cause flu in the
next year before deciding on the next vaccine
There is a lot of interest in developing a universal flu vaccine - there are
attempts to produce antibodies against the parts of the spike proteins that are conserved
How many serotypes of poliovirus are there and what type of vaccine was produced for polio?
There are THREE serotypes of poliovirus
This required a TRIVALENT POLIO VACCINE
One serotype has been eliminated from the world
What are the features of dengue haemorrhagic fever (DHF)?
Leakage of plasma from capillaries leads to: Increased haematocrit Increased red cell count Decrease in protein Tendency to severe bruising and bleeding
Consequences of Antigenic Variation in Dengue Virus
Dengue haemorrhagic fever (DHF) is responsible for a lot of hospitalisation and fatalities each year
It causes leakage of plasma from the capillaries
The loss of fluid from the blood leads to an increased haematocrit and increased red cell count and a decrease in protein in the blood
Tendency to severe bruising and bleeding
Patient deteriorates even after the fever drops: shock
Treat with IV fluids
What is the treatment for DHF?
IV fluids
How many serotypes of dengue are there?
Dengue exists as FOUR serotypes
Antibody generated against a previous dengue infection can bind to but NOT
neutralise the current dengue infection
It can lead to ANTIGEN DEPENDENT ENHANCEMENT (ADE) causing Dengue
Haemorrhagic Fever
In other words, if you have been infected with one serotype of dengue, you will develop antibodies against it. Then if you get infected by another serotype, your antibodies will bind to but not neutralise the new serotype of dengue and it will cause antibody dependent enhancement of the current dengue serotype causing dengue haemorrhagic fever
Explain the significance of the presence of multiple serotypes ofdengue with regards to the pathogenesis of DHF.
Infection with one serotype will cause antibody production Antibody generated against this serotype will bind to but NOT neutralise infection with another dengue serotype This can lead to ANTIGEN DEPENDENT ENHANCEMENT (ADE) causing Dengue Haemorrhagic Feve
What can viruses do to glycoprotein antigens that hinder antibody access to the antigens?
Heavily glycosylate the antigens
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
RECAP from interferon lecture: VP35 and VP24 stop the innate immune system from seeing ebola
Ebola pretends to be an apoptotic body so it gets rapidly taken up by cells and doesn’t hang around outside where it could get detected by antibodies
Ebola also synthesises soluble glycoproteins that act as an ANTIBODY DECOY
Soluble glycoprotein is the default coding for the glycoprotein (GP) gene
Full length GP is made by polymerase stuttering
Other than being an antibody decoy, soluble glycoprotein is also
immunosuppressive and inhibits neutrophils
GP2 and retrovirus glycoproteins have an immunosuppressive peptide
Reston virus version is only suppressive in macaques
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) NOTE: GP2 and retrovirus glycoproteins also have an immunosuppressive peptide
Which virus is only suppressive in macaques?
Reston virus
How does Measles infect cells?
MEASLES vaccination had a much larger impact on childhood mortality than
expected
Measles infects CD150 (SLAM) positive cells, which includes memory
lymphocytes and ERASES IMMUNOLOGICAL MEMORY
So a measles virus infection can result in a 2-3 year decrease in immunological
memory that leads to morbidity and mortality from other diseases
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 a 2-3 year decrease in immunological memory that leads to morbidity and mortality from otherdiseases
E - viruses that are adapted to the host species are likely to be able to control their innate immune response
B - e.g. signalling molecules in the innate immune system
- C
- D - HIV encodes Vif, which counteracts IFN
