Viral evasion of the host immune response Flashcards
What are virus proteins easy targets for and why?
Their proteins are easy targets for processing and presentation by MHC because they are intracellular pathogens
What clears viral infection?
Cellular immunity but its is short lived
Why are internal viral proteins targets for cellular immunity?
As they are intracellular, they tend to vary less than surface antigens
What must viruses evade to survive?
Cellular immunity
What happens to foreign peptides inside a cell?
They will be chopped up into smaller peptides inside the proteasome
What happens to the smaller peptides formed from the proteasome?
They get fed in through the TAP proteins into the endoplasmic reticulum where it gets loaded onto an MHC class I molecule
What happens to the loaded MHC class I molecule?
It moves to the cell membrane where the viral peptide can be recognised by T cell receptors on the surface of cytotoxic T cells
What does the T cell do upon recognising viral peptides?
Kills the virus infected cell
How does EBV evade cellular immunity?
It expresses a protein called EBNA1 that cannot be cut into smaller peptides in the proteasome- so EBV can exist in the cell but its proteins are not processed
How does HSV evade cellular immunity?
It encodes ICP47 which blocks access of processed peptide to TAP
How does CMV evade cellular immunity?
It encodes US6 which stops ATP binding to TAP, which is required for TAP to be able to transport peptides across the membrane
How does CMV prevent MHC transport?
It encodes US3 which binds to tapasin and prevents peptides being loaded onto MHC
How does adenovirus E3-19K prevent MHC transport?
It prevents recruitment of TAP to tapasin and retains MHC in the ER
How does Kaposi sarcoma herpes virus kK3 protein evade the immune system?
It induces polyubiquitination and internalisation of MHC so virus peptides won’t be presented to T cells
What does the lack of MHC by a cell normally lead to?
Detection by NK cells and they are killed
How do viruses that disrupt MHC presentation evade NK cells?
These viruses encode MHC analogues or up regulate MHC. The virally encoded MHC is useless and doesn’t trigger the immune response but it does fool the NK cells into thinking that cells are normal
How does HIV evade cellular immunity?
It targets CD4+ T cells and depletes the ability to support an immune response
How does ebola virus evade cellular immunity?
It results in destruction of target dendritic cells and macrophages by direction infection and of T cells by a bystander response
What percentage of people are infected by HCMV and in who does it cause a problem?
80-90% are infected but it only causes a problem in people that are immunocompromised
When does HCMV virus need to be eliminated from bone marrow cells?
Before transplantation because otherwise it will reactivate in an immunosuppressed transplant recipient
What does UL138 protein produced by CMV infected cells lead to?
Loss of MRP-1 from infected cell surface
What is MRP-1?
Transporter that transports toxic drugs out of cell
What does loss of MRP-1 transporter lead to?
Accumulation of certain molecules in infected cells including the toxic drug vincristine
How are cells from a donor treated before transplantation to eliminate CMV?
They can be vincristine treated- it has improved the outcome in the bone marrow transplant
What is influenza antigenic drift?
Continued rapid evolution driven by antigenic pressure from the host
What is influence antigenic shift?
Introduction of new subtypes from animal source
What are serotypes?
Differently genetically stable forms of disease that can cocirculate in humans
What is the result of the antigenic drift of influenza?
The influenza vaccine must be updated every year
How many subtypes are there of influenza?
4
How would a universal flu vaccine be developed?
Antibodies produced against parts of the spike proteins that are conserved
How many serotypes are there of rhinovirus?
More than 120 antigenically distinct serotypes- impossible to make a vaccine against
How many serotypes are there of poliovirus?
Three- requires a trivalent polio vaccine
How does HIV evade antibodies?
The HIV env spike gp120 resists neutralisation because:
Large space between spikes prevents Ab cross linking
Extensive glycosylation masks antibody epitopes
Functionally important parts of the molecule are poorly accessible
What is the consequence of antigenic variation in dengue virus?
Dengue haemorrhagic fever is responsible for a lot of hospitalisation and fatalities- it causes leakage of plasma from capillaries and this loss of fluid leads to increased haematocrit and increased red cell count and decrease in protein in blood. There is a tendency to severe bruising and bleeding. Patient deteriorates even after the fever drops
It is treated with IV fluids
How many serotypes of dengue are there?
Four
How do antibodies enhance dengue?
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
How do some viruses evade the antibody response?
They have glycoprotein antigens that are so heavily glycosylated that antibody access is hindered e.g. HIV and ebola (looks more like human mucin because they are so glycosylated)
How does ebola virus evade the antibody response?
Their particle membranes have a high content of phosphatidyl serine lipids making them look like apoptotic bodies. As they look like apoptotic bodies, they are rapidly taken up macropinocytosis, away from antibody surveillance. It also has a long filamentous shape which has lots of folds so glycoproteins may be inaccessible in these viral pockets making it harder for antibodies to neutralise the glycoprotein.
How does VP35 and VP24 help ebola?
It stops the innate immune response from seeing ebola
What does ebola synthesis to act as an antibody decoy?
Soluble glycoproteins- it is the default coding for the glycoprotein gene, it is also immunosuppressive and inhibits neutrophils
How effective was measles vaccination and why?
It had a much larger effect than expected on childhood mortality. Measles infects CD150 (SLAM) positive cells, which includes memory lymphocytes and erases immunological memory, so meals virus infection can result in 2-3 yr decrease in immunological memory that leads to morbidity and mortality from other diseases
