Viral Evasion of host immunity Flashcards
Describe the relationships between virus and cellular immunity
Viruses are intracellular pathogens and 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 of cellular immunity. They tend to vary less than surface antigens- more conserved across serotypes than antigens
Viruses that persist must evade cellular immunity. The family of herpes viruses are the classic examples.
What is the difference between cellular immunity and humoral immunity
Cellular immunity- can see inside cells via MHC- T-cell mediated
Humoral immunity - B cell mediated- antibodies against antigens expressed on the cell surface of viruses
Describe the process of the presentation of viral peptides on MHC class 1
Viral peptides (both structural and non-structural) 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 B2-Microglobulin and it will then move to the cell surface where T cells can recognise the antigen- via Golgi processing
The TCR will then recognise MHC presented with the viral peptide and CD8 will destroy the infected cell via perforins - preventing the virus from infecting other cells
State some viral proteins that evade antigen loading onto TAP
EBV EBNA1 cannot be processed by the proteasome- lots of glycine and alanine- can’t be recognised
HSV ICP47 blocks access of the processed peptide to TAP
CMV US6 stops ATP binding to TAP preventing translocation
Describe how viral modulation of tapasin function can prevent function of MHC transport
CMV US3 binds tapasin and prevent peptides being loaded to MHC
Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum
Describe how viruses can interfere with the MHC presentation at the cellular surface
KSHV kK3 protein induces polyubiquitinylation (lys-63 linked) and internalization of MHC.
From the internalized endosome, MHC is passed to lysosomes where it is degraded.
Clathrin-1 and epsin-1 dependent internalisation
Describe how HPV counters both the innate and cellular immune response
HPV makes E7- which binds to STING and prevent the cGAS sensing of DNA
E6 binds to and sequesters the dimerisation of E6 and E7- preventing its translocation to the nucleus.
E6 binds to TYK2- interfering with the Bak/STAT signalling of IFNs
E7 binds to IRF9- meaning that the the dimerised phoshprylated STATs cannot translocate to the nucleus to stimulate the production of ISGs
So interferes with both IFN production and signalling to interfere with the innate immune response
E5 prevents loading of the MHC 1 to the plasma membrane and also MHC 2
E7 also prevents the transcription of MHC-1 and TAP
Describe virus-mediated immunosuppression, using measles as an example
Measles vaccination has a much larger impact on childhood mortality than expected if it only protect against measles virus itself.
MV infects CD150 positive cells, including memory lymphocytes and erases immunological memory.
Measles Virus infection results in a 2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.
You are like a naive baby again
Describe the importance of vaccination against measles
The introduction of measles vaccine was associated with up to 90% reduction in childhood mortality in poorer settings.
There is only one serotype of measles!
This is of particular importance today where, especially in wealthy nations, reduced opportunistic infections during acute measles immunosuppression, added to the comparative rarity of infection, has led to a public view of measles as a benign childhood disease…
Describe how viruses avoid NK killing by missing self mechanism
Normal healthy cells display MHC at their surface.
Cells that don’t display MHC are detected by NK cells and killed.
Viruses that disrupt MHC presentation would end up being killed by NK cells.
Viruses encode MHC analogues (CMV gpUL40) or upregulate MHC.
Thus preventing killing by NK cells and cytotoxic T lymphocytes
Summarise antigenic variation
Continued rapid evolution driven by antigenic pressure from host :influenza antigenic drift, HIV quasispecies- so long to replicate- mutations in replication creates a quasispecies.
Introduction of new subtypes from animal source: influenza antigenic shift
Existing as different genetically stable serotypes that cocirculate in humans
e.g. rhinovirus, 100s of serotypes
poliovirus, 3 serotypes
Dengue, 4 serotypes
Consequence for vaccination- need to vaccinate against all serotypes
Ultimately, what is the difference between antigenic drift and antigenic shift
Antigenic drift- During viral replication, mutations can occur in the HA or NA, leading to changes in the antigenic nature of these glycoproteins. The resulting strains are only partially attacked by our immune system, resulting in milder disease in adults who have previously acquired antibodies. Major mutational changes usually result in altered codon reading frames and a nonviable virus.
Antigenic shift: There is a complete change of the HA, NA or both. This can only occur with Influenza type A because the mechanism involves the trading of RNA segments between animals and humans. When 2 influenzae types co-infect the same cell, undergo replication and capsid packaging, RNA segments can be mispackaged into another virus. The virus now yields a new NA or HA glycoprotein that has never been exposed to a host immune system anywhere on the planet.
Describe antigenic drift
Continued rapid evolution driven by antigenic pressure from the host
The viruses are RNA-dependent polymerases- no repair- very error prone- lead to mutations in the amino acids that encode glycoproteins (NA and HA)- the fittest strains will survive- i.e those who have a HA or NA which cannot be recognised by host antibodies- which would neutralise them and prevent them form entering host cells.
What are the two parts of viruses
Head domain- this contains epitopes which the immune system can recognise- least conserved part to compete with the immune system
Stalk domain- more conserved part- virus needs this to function- so rarely mutates.
Describe the need to update flu vaccines every year to best-represent circulating strains
Vaccine updated every year to best represent the circulating strains- because of antigenic drift
Influenza A virus H3N2 has evolved by antigenic drift in humans for 50 years- use antigenic cartography- culture and sequence the antibodies from those who had the flu- to map the antigen that the virus expressed- if it differs massively from others- need to include it in future vaccines
H3N2 drift is rapid and many clades co-circulate.
There have been 28 vaccine updates for H3N2 viruses since 1968
Six updates in the last 10 years.
Genetic analysis of phylogenetic trees- see which strains are circulating that year- to determine which should be included in the vaccine
