Micro 5: Viral evasion of host immunity Flashcards
How can the immune system detect viruses
Viruses are intracellular pathogens and so their proteins are easy targets for processing and presentation by MHC.
What parts of the virus is an immune response mounted against
The MHC can present all parts of the viruses, not just the outside. The antibodies will be made obviously to surface molecules But the inside of the virus can be preseted on MHC and this can trigger CD8+ T cell to kill the virally infected cell
What is more variable, internal viral proteins or surface molecles?
Internal viral proteins can be targets of cellular immunity. They tend to vary less than surface antigens.
T/F a virus can be chronic without interfering with cellular immuity
F… Viruses that persist must evade cellular immunity
Give an example of a family of viruses that evade cellular immunity
. The family of herpes viruses are the classic examples.
Outline presenation of internal peptides inside a cell
Proteins in cell chopped up by proteosome, peptides transported into the ER where they are loaded onto MHC class 1 and the b2-microglobulin is added This is then transported through the golgi apparatus and displayed on the surface of the cell The peptide being presented can then be seen by a T cell receptor on a T lymphocyte
Which cells in th ebody expresses class 1 MHC
Both
What activates the T cell
The MHC 1, TCR, foreign peptide and CD8 is important too
How do HSV 1 prevent interfere with cellular immunity
HSV ICP47 blocks access of the processed peptide to TAP
How does EBV evade cellular immunity
EBV EBNA1 cannot be processed by the proteasome so the viral protein cannot be chopped up and put into the ER so it cannot be presented in MHC class 1 to activate T cell
What is the name of the protein that transports peptides into the ER
TAP
How does CMV evade cellular immunity
CMV US6 stops ATP binding to TAP preventing translocation .CMV US3 binds tapasin and prevent peptides being loaded to MHC (i.e. cuts off the energy to TAP so peptides can’t get into the ER and thus cannot be associated with the MHC molecules and cannot be presented to the T cells)
Which molecule assists in loading the peptide onto the MHC
Tapasin
How can adenovirus effect cellular immnity
Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the endoplasmic reticulum
How does the KSHV (HHV8) evade cellular immunity
KSHV kK3 protein induces polyubiquitinylation and internalization of MHC. From the internalized endosome, MHC is passed to lysosomes where it is degraded. Cannot present viral proteins to the T cell
What type of virus is the HPV
DNA virus, but with shorter genome than herpes
How does HPV evade the immune response
Both cellular and innate response Just note that because HPV has a small genome, its proteins often do diverse range of functions E6/E7 are oncogenic (interfere with cell cycle), but they are also binding to proteins involved in the interferon detection pathway (cGAS, STING etc) and the IFN-a effector pathway (innate). E7 also prevents transcription of MHC and TAP proteins E5 holds onto the MHC class 1 molecule in the ER and the golgi and prevents it from being transported to the surface (cellular)….. BUT think about the consequence of loss of MHC
What is the human response to lack of MHC on cells
This makes immune system think there is virus in the cell So loss of MHC1 activates NK cells 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.
How do viruses get around the NK response which kills them if they interfere with MHC Give an example
Viruses encode MHC analogues (CMV gpUL40) or upregulate MHC.
What are virus vaccines usually trying to achieve
An antibody response
What is antigenic drift, vs antigenic shift
Continued rapid evolution driven by antigenic pressure from the host= antigenic drift Introduction of new subtypes from animal source= antigenic shift
Give example of antigenic drift and shift
Drift: influenze antigenic drift Shift: influenza antigenic shift
What is a quasi species in relation to antigenic drift What is the difficulty for treatment
It’s when HIV replicates inside you it and spits out lots of different variants of the virus (=antigenic drift) The body can’t mount reponses against each subtype of the virus and contain it because of all of the different surface molecules
Outline the differences in the number of serotypes with viruses and the consequences for vaccination
There is antigenic variation existing as different genetically stable serotypes that cocirculate in humans Rhinovirus- 100s Polivoris- 3 Dengue- 4 Consequence is theat the polio and dengue viruses nit to be trivalent and quadrivalent respectively The rhnovirus it is impossible to get a vaccine to promote immunity against so many serotypes… and not worth it cos only common cold anyway
What drives influencza antigenic change
EVOLUTIONARY PRESSURE DRIVES ANTIGENIC CHANGE IN INFLUENZA ABs bind to viruses and is neutralised
What do ABs bind on influenza
Haemagglutinin= major influenza viral spike antigen It has head and stalk domain. A trimer
Outline the conservation of haemagluttinin
There are some AAs which are highly conserved and some which are highly variable between different haemagglutinin molecules The head domain (which pokes out most into the external environment) is highly variable
Why is the head domain likely to be variable in the haemagglutinin molecule
So that the B cells don’t mount an immune response to it (i.e. the AA are constantly changing so that previously formed ABs cannot bind them) =ESCAPE. This is the basis of antigenic drift
What is the head resonsible for in haemagluttinin
Binding to the cells influenza wants to infect (i.e. respiratory epithelium) The target of B cells to make antibodies against it =HA1
How much do AAs have to change within the haemagglutinin molecule in order to prevent preformed AB binding
If the haemagglutinin has only a couple of AAs change, it will escape the preformed antibodues
Which part of the haemagluttinin has conserved AAs and why
The stalk (=HA2) Maybe because the protein is so critical to the virus that it cannot be varied (not selected for) OR no evolutionary pressure yet (only a tiny fraction of the antibodies actually see the stalk, they se the head)
How could a universal influenza be developed
Develop AB to the part of the haemagglutinin which is conserved and integral to its function and thus present on every haemagglutinin thus alowing us to target every strain of influenza
How do we know whether we need to update flu vaccine
You look at the variable part of the haemagglutinin molecule on Influenza A virus H3N2 (which is the virus causing seasonal flu) To see if they have changed enough such that ABs produced from pre-administerd vaccines will not longer be specific enough to bind the haemagglutinin You look on antigenic cartography
Why is it so difficult to vaccinate against influenza
H3N2 antigenic drift is rapid and many clades co-circulate
Outline the process of deciding which flu vaccne to make
Collection of influenza samples, genetics and antigenic characterisation, WHO recommends vaccine strains These vaccine strins are then grown in bulk
What happens if the correct flu strain isn’t chosen for vaccine
The selected strain could be a poor match with the predominant circulating virus. Low efficacy
What area of haemagluttinin does ‘broadly neutralising Ab’ attack?
Broadly neutralising Ab (bnAb) attacking stem region
Is the the bnAb currently used?
No, Current vaccines generate specific Ab responses raised against immunodominant HA1 epitopes at five antigenic sites (Sa, Sb, Ca1, Ca2, Cb) Basically the conserved regions of the haemagglutnin has been found but the immune system hasn’t really developed many T cells against it because it doesn’t see it enough (the head is the area exposed to the immune system) You need to get the immune system to see the conserved area if you want to develop the universal influenza vaccine that tackles all types of the virus
Ideas for development of universal influenza vaccine (i.e development of the bnAb antibody which targets HA2?)
- Headless HA 2. Hyperglycosylating HA1 head domain (so that the immune system can’t see HA1 and just focuses on HA2) 3. Peptides against fusion peptide (FP) and ectodomain (EHA2) 4. Ferritin based nanoparticles displaying HA 5. Sequential immunization with Chimeric HA
How could ferritin based nanoparticles work in influenza
displaying HA but with more space etween HA molecules and this then allows more room for B cells to come in and recognise the antigen
How could Sequential immunization with Chimeric HA help to develop universal influezna vaccine
Could keep changing HA1 and keep HA2 conserved when giving booster vaccines This will make the immune system focus on the conserved part not the variable part
Which part of HIV helps it to evade antibodies
HIV env spike gp120 resists neutralization
How does gp120m the HIV spike molecule, evade neutralisation
- Large space between spikes prevents Ab crosslinking 2. Extensive glycosylation masks antibody epitopes 3.Functionally important parts of the molecule are poorly accessible, CD4 binding site, redundant amino acids are visible to B cell receptor and antibodies. 4.Huge variation in the redundant amino acids means most antibodies are highly clade specific.
Why can large spaces between spikes be a positive and negative thing for viruses
Problem for the virus: Allows lots of spaces for ABs to come in and bind the viral spike proteins (i,,e the basis for the ferritin nanoparticle influenza vaccine relies on this) Benefit for the virus: It means that Abs which bind the viral proteins are too far apart to cross link So Abs are less efficient
What molecule is more glycosylated- gp120 or haeamagglutiin
gp120
What type of molecule is gp120
trimer
Do bnAbs exist for HIV?
bNabs produced as biological therapeutics can control viral load. but haven’t yet been developed
T/fAntibodies that can cross react with many HIV strains do exist alongside virus in people who control infection.
T
bNab controls viral load but what is the problem with it
That the conserved regions in the gp120 may just mutate (i.e. it might be that they are not necessary for viral function, and that the virus just didn’t have selective pressure before to chage those areas)
Differentiate the antigenic drift in human rhinovirus with influenza
So the evolutionary process for the common cold virus happened many years ago but there are hundreds of serotypes With influenza, the process is still happening such that there are still new strains being produced The reason we cannot vaccinate for the common cold virus is that there are so many serotypes The reason we cannot vaccinate for flu is that there are new serotypes every year, and many strains cocirculate
Outline the problems with the sabin vaccine for polio
For the live attenuated Sabin vaccine, administration of all 3 at once resulted in virus interference and poor response to one component. This meant that you could still be infected with the type against which the body didn’t respond to in the vaccine However you just needed to adjust the ratios to increase the amount of weedy virus that you injected One serotype has been eradicated from the world so yu only really need the body to respond to two serotypes now anyway
What is teh consequence of antigenic variation of denuge virus
Dengue haemorrhagic fever.
What causes dengue haemorrhagic fever with regardto antigenic variation
Dengue Virus exists as 4 different serotypes. If you are infected with one serotype, you develop Abs to it But if a second serotype then infects you, then antibody generated against the previous serotype can bind but not neutralize the new serotype Instead, the Ab-new serotype complex binds to monocytes via the Fc receptor And the new serotype can then access the monocytes and replicate inside them!
Why does infection of monocytes by a second dengue serotype infection lead to DHF
- New tropism for the virus to grow in (rapidly grows) 2. Because the monocyte is an APC, then it can release loads of cytokines and cause cytokine storm
What does dengue haemorrhagic fever result in How is it detected Treatment
Leakage of blood plasma from capillaries (due to cytokine storm) Detected by increase in red cell count and decrease in protein level in blood. Tendency to severe bruising, and bleeding. Patient deteriorates even after fever drops; shock. Treat with iv fluid replacement.
What receptor does measles use and thus what is its tropism
MV infects CD150 (=SLAM) positive cells, including memory lymphocytes and erases immunological memory.
What is the longer lasting consequence of measles infecion
2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.
