Viral evasion of host immunity Flashcards
what kind of pathogens are viruses?
and what does this mean for presentation via the MHC?
- Viruses are intracellular pathogens
- therefore their proteins are easy targets for processing and presentation by MHC
how long does cellular immune response to viral infections last?
- Cellular immunity clears viral infection but is short-lived
why is cellular immunity an issue for internal viral proteins?
- Internal viral proteins can be targets for cellular immunity via the MHC and antibody response
- they are intracellular antigens and therefore they vary less than the surface antigens
- therefore in order to persist they must evade cellular immunity
how do MHC Class I present viruses?
- the foreign peptides inside the cell (eg. viral peptides) get chopped up into small peptides inside the proteasome
- they are fed through the TAP protein into the endoplasmic reticulum
- the tapasin protein loads them onto the MHC I molecule
- the MHC molecule then moves to the cell membrane
- there the viral peptide is recognized by the T cell receptors
- the T cells are then able to kill the virus-infected cell
how does the Epstein Barr Virus evade antigen presentation via preventing antigen loading to TAP?
- EBV expresses a protein called EBNA1
- this cannot be cut up into smaller peptides, therefore, it can exist without being detected
how does the Herpes Virus evade antigen presentation via Evasion of Antigen Loading to TAP?
- HSV encodes ICP47
- this blocks access of the processed peptide to TAP protein
- so it cant be loaded into the endoplasmic reticulum
how does the CMV evade antigen presentation by modulation of TAP function and Tapasin function?
- CMV encodes US6 which stops ATP binding to TAP
- this means that TAP is not able to transport peptides across the membrane
- CMV also encodes US3 which binds to tapasin and prevents peptides being loaded onto MHC
how does Adenovirus E3P19K evade antigen presentation by modulation of Tapasin function?
- Adenovirus E3P19K prevents recruitment of TAP to tapasin and also retains MHC in the ER so it cannot present to the T cell
how does Kaposi Sarcoma Herpes Virus interfere with MHC presentation at the cell surface?
- Kaposi Sarcoma Herpes Virus induces polyubiquitination (this kills the protein) and internalization of MHC
- if the MHC isn’t present at the cell surface then the virus peptides won’t be presented to T cells instead the MHC is passed onto lysosome and is degraded
how do viruses avoid natural killer cells by the missing self mechanism?
- all normal cells display MHC on their cell membranes
- if they don’t have MHC then they are detected and killed by natural killer cells
- so when viruses disrupt the MHC presentation they would get killed by natural killer cells
- Therefore to get around this viruses encode MHC analogues or upregulate MHC
- this new viral MHC is actually useless bu it avoids the NK cells
what does the measles infection do to the immune system?
- it is called Virus mediated Immunosuppression
- the measles infection erases immunological memory in the child for the next 2 to 3 years
- therefore even if the child doesn’t die of measles they might die of something else due to having limited immunity
why is the measles vaccine so effective?
- it does not only protect against the measles virus
- it also prevents the loss of the immune system therefore conserving immunological memory in the following 2-3 years
how do some viral infections use the destruction of T cells?
- HIV targets CD4+ T cells, therefore, preventing an immune response
- Ebola virus infection results in the destruction of target dendritic cells and macrophages by direct infection
- T cells are also destroyed as a bystander response
how might we use knowledge of how viruses manipulate infected cells to improve medical outcomes?
using the example of HCMV and CMV?
- HCMV only affects those who are immunocompromised
- so in bone marrow transplants, the virus needs to be eliminated from bone marrow cells before they are transplanted into the immunocompromised
- UL138 protein is produced by HCMV and it leads to loss of MRP-1 from the infected cell surface
- MRP-1 is a transporter that transports toxic drugs out of the cell
- the loss of the MRP-1 transporter leads to accumulation of molecules in cells infected by HCMV
- so, for example, the toxic drug VINCRISTINE
- the donor is treated with vincristine before transplantation to eliminate the CMV cells
- this has improved bone marrow transplant results
what is Influenza Antigenic DRIFT?
- continued rapid evolution driven by antigenic pressure from the host
what is Influenza Antigenic SHIFT?
- introduction of new subtypes from an animal source
- this is completely new to humans
what are different genetically stable serotypes?
- these viruses don’t change but there are many serotypes of them eg. rhinovirus, poliovirus, dengue
- they co-circulate in humans
why does the influenza vaccine get updated each year?
- Because of the antigenic drift of influenza, the virus keeps looking different so the vaccine needs to be updated every year
how many serotypes does influenza exist as?
- influenza exists as four different serotypes
- these drift year on year
how is the serotype chosen to be put into the vaccine?
- each year WHO tries to predict which influenza serotype is most likely to cause flu that year
- but often it is not that accurate
what is the universal flu vaccine?
- doesnt actually exist
- an ideal vaccine that protects against all types of flu
- there are attempts to produce antibodies that attack the stalk of the virus which is always conserved
- however antibodies do not normally act this way which is why it’s difficult
what does the human rhinovirus cause? what is the variation in the Human rhinovirus?
- Human rhinoviruses cause the common cold
- They exist as more than 120 antigenically distinct serotypes that all circulate
- its impossible to make a vaccine against all of them
how is HIV able to evade antibodies?
- Some viruses have glycoprotein antigens that are so heavily glycosylated so that the antibody access is hindered
- the virus looks more like human mucin than viral antigens
- also functionally important parts of the molecule are poorly accessible, CD4 binding site
- so they are not able to be vaccinated against
how might we design an HIV antibody? what is the issue?
- we could genetically modify the antibody response to attack the stalk of the spike region
- the issue is the virus keeps evolving therefore it is hard to make a vaccine that works
how many serotypes of poliovirus?
how does the polio vaccine work?
- There are three serotypes of poliovirus
- this requires a trivalent poliovirus
- this has resulted in one serotype being eliminated from the world
how many serotypes does the Dengue virus have?
- exists as 4 different serotypes
what is the consequence of the antigenic variation of the dengue virus?
- if you get infected by one type of serotype of dengue fever you just get a slight fever
- if you get infected by another serotype then you might develop a hemorrhagic fever (very dangerous)
why does this Haemorrhagic Fever happen?
- 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 neutralize the new serotype of dengue
- this allows the virus to replicate more and therefore have a much greater response on the person
- this is called antibody dependent enhancement of the current dengue serotype
what is Dengue haemorrhagic fever ?
- It causes leakage of plasma from the capillaries
- the loss of fluid from the blood causes increased hematocrit and increased red cell count and a decrease in protein
- therefore there is severe bruising and bleeding
- high mortality
- treat with IV fluids
why is developing a vaccine for Dengue fever dangerous?
- antibody-dependent enhancement
- the vaccine might not neutralize the dengue fever and stop its replication
- therefore it might just prevent the immune reaction to the serotype
- , therefore, making people more susceptible to the hemorrhagic fever
