Viral Evasion of Host Immunity Flashcards
example of a virus that evades cellular immunity
herpes simplex virus
how does a viral protein end up being presented on an APC?
- viral protein
- chopped up by proteasome
- enters ER via TAP
- binds to MHC in ER
- MHC-antigen complex shifted to Golgi
- transported to surface for recognition by T cell
why may it be preferred to target internal viral protein than surface antigens?
internal proteins don’t vary as much as surface antigens
how do EBV, HSV and CMV evade being loaded to TAP?
EBV= EBNA1 (odd protein) cannot be processed by the proteasome.
HSV= ICP47 blocks access of processed peptide to TAP.
CMV= US6 stops ATP binding to TAP thus preventing translocation.
how do CMV US3 and adenovirus modulate tapasin (involved in MHC I maturation in ER) and therefore prevent MHC transport?
CMV= US3 binds Tapasin and prevents peptides being loaded to MHC.
Adenovirus= E3-19K prevents recruitment of TAP to Tapasin and retains MHC in ER.
how does KSHV interfere with MHC presentation at the cell surface?
kK3 protein induces polyubiquitinylation and internalisation of MHC.
From internalised endosome, MHC is passed to lysosomes for degradation
how do self-cell survive murder?
all normal healthy cells display MHC as the surface
those that don’t are killed by NK cells
why do virus infected cells end up being killed by NK cells? how do they avoid this?
they disrupt MHC presentation
however, viruses can encode MHC analogues/MHC mimics (CMV gpUL40) or upregulate MHC so to avoid detection and destruction
when is CMV infection a problem?
A frequent problem for transplant recipients during immunosuppression
Virus needs to be eliminated from bone marrow cells of the transplant recipient before transplantation
CMV evades immunity via production of the UL138 protein leads to loss of MRP-1 (a molecule that can transport toxic substances out of cells) from the infected cell surface so toxic molecules accumulate
how does measles evade immunity?
- bind and infect cells that express SLAM (CD150)
- This is found on memory cells so infection leads to the erasing of immunological memory
(a 2-3 year decrease in memory therefore increased mortality from other diseases)
what leads to antigenic variation in viruses?
o Continued rapid evolution driven by antigenic pressure from host
o Introduction of new subtypes from animal sources (zoonoses like influenza causing antigenic shift)
o Existing as different stable serotypes that co-circulate in humans
o Consequence of vaccination.
How does continued rapid evolution driven by antigenic pressure from host lead to antigen variation?
HIV as a latent virus leads to mutations overtime that form quasi species in the infected person during dormancy
Influenza does this year to year so vaccines are updated annually and multivalent seasonal vaccines
what is antigenic drift?
Antigenic drift is a kind of genetic variation in viruses, arising by the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies don’t recognize.
what is antigenic shift?
Antigenic shift is the process by which two or more different strains of a virus, or strain of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains.
name viruses and how many serotypes they have
- rhinovirus= 160
- polio=3 (one has been completely eradicated, vaccine is trivalent)
- dengue= 4
what is the trouble with a trivalent polio vaccine?
The live-attenuated Sabin vaccine resulted in virus interference and poor response to one component.
why is the rhinovirus, causing the common cold, almost impossible to vaccinate against?
has 160 serotypes
name and describe the main antigen on influenza and its structure
- haemagglutin
- highly variable at the head domain (also called the variable domain/HA1)
- the stalk (HA2) is not as variable and called the Conserved Domain
how has the structure of influenzas HA antigen contributed to the difficulty of creating a vaccine?
vaccines that have been created have mainly targeted the highly variable HA1/variable region
mutants of the head domain mean vaccines become redundant every year
what can be done to make vaccines effective against influenza
synthetic vaccines need to be designed to target the conserved region that is not variable (stalk/HA2)
what were the attempts for vaccinating against influenza?
- using headless HA
- hyperglycoslating HA1 so antibodies are forced to recognise HA2
- increasing stalk accessibility by using nanoparticles
why has it been hard to vaccinate to HIV in reference to its antigens?
- gp120 spikes resist neutralisation because they are wide apart so antibodies can not cross link
- extensive glycosylation masks Ab epitopes
- functionally important parts of antigen are poorly accessible (CD4)
similar case to influenza
how is HIV load controlled?
using BNabs (Broadly Neutralising Abs) that prevent HIV entering host cells
what mechanism leads to dengue haemorrhagic fever?
Antibody-Dependant Enhancement (ADE
explain Antibody-Dependant Enhancement (ADE) in dengue
- dengue has 4 serotypes that can infect you
- a previous infection by one serotype means antibodies are generated for it
- these can bind to a 2nd infection by a second serotype BUT do NOT neutralise the second serotype
- this causes the formartion of immune complexes
- the immune complexes are detected by monocytes Fc receptor and are internalised
- the virus can now replicate and has an enhanced tropism
why may a univalent vaccination be dangerous in diseases with multiple serotypes?
vaccination for one serotype means antibodies for one serotype exist but these are not capable of neutralising the second serotype so form immune complexes that can be used to by the virus to gain access into cells
describe the effects of dengue
- causes leakage of blood plasma (fluid) from capillaries
- hypotension
- reduced RBC count
- cytokine storm
- ADE
what are 3 techniques used to evade antibodies?
1) Glycoprotein antigens
– these are so heavily glycosylated (mucin-like) that antibody access is hindered – e.g. HIV.
2) Apoptotic body disguise
– Ebola virus particle membranes have a high phosphatidl serine lipid content that makes them look like apoptotic bodies so are taken up by micropinocytosis and hidden from the immune system.
3) Viral filaments
– viral filaments are hard for Abs to neutralise as GLPs inaccessible in folded packets.
what proteins stop the detection of ebola by the immune system?
VP35 and VP24
what is the effect of having soluble glycoproteins on the cell surface?
soluble GPs are immunosuppressive and inhibit neutrophils.
synthesised by ebola
what errors in RNA viruses promote antigenic variation?
error prone polymerases
they are more error prone that in DNA viruses
what is the simple definition of antigenic drift?
spontaneous mutations that slightly change proteins
leads to epidemics
give an example of a virus that undergoes antigenic drift
influenza virus
changes its haemagglutin and neuraminidase proteins
therefore a new vaccine is required every year
what is the simple definition of antigenic SHIFT?
exchange of RNA segments between human and animals viruses
leads to pandemics
e.g SARS-CoV-2
what does antibody dependent enhancement cause?
example of virus
haemorrhagic fever
e.g in dengue
which class of MHC presents endogenous peptides including viral peptides?
MHC class I
examples of viruses that can interfere with MHC loading of viral peptides and presentation
- adenovirus (gene expression, transfer to Golgi)
- HSV (TAP)
- hCMV (TAP, transfer to Golgi)
- mCMV
CMV= cytomegalovirus
how does CMV US36 affect TAP?
prevents ATP binding to TAP
how does EBV evade presentation by MHC class I?
it cannot be cleaved by the proteasome
what is the role of tapasin?
mediates interaction between MCH Class I and TAP
how does CMV US3 prevent antigen loading onto MHC?
binds to tapasin
how does adenovirus E3-19K prevent MHC transport to Golgi?
prevents recruitment of TAP to tapasin
retains MHC in the endoplasmic reticulum
how does Kaposi sarcoma affect MHC presentation on the cell membrane?
polyubiquinates the MHC molecules
this causes the MHC to be internalised and broken down
remember: HIF factors in angiogenesis becomes ubiquinated and then broken down
ubiquination –> break down
what happens to cells that lack MHC expression?
they are killed by NK cells
how do cells overcome being killed by NK cells?
they produce decoys that are analogues to MHC
viruses that employ decoys to avoid NK cell killing them
CMV gpUL40
others can up regulate MHC
how does HIV evade NK killing?
glycosylating the functionally important parts so they become poorly accessibly
what feature of HIV is heavily glycosylated so the virus becomes difficult to access?
Gp120 antigen
what makes it difficult to create antibodies against HIV?
huge variation and mutation rate
what effect does measles have on immunity?
erases immunological memory
fucks memory cells
what MHC presents viral peptides?
MHC class 1
presents to antigen specific T cells
how does HSV interfere with MHC processing and presentation?
ICP47 prevents the loading of peptides in to the transporter protein complex TAP.
how does human cytomegalovirus US3 interfere with MHC processing and presentation?
US3 binds to tapasin MHC class I and prevents it transport to the cell surface.
how does HCMV and adenovirus use proteins to interfere with MHC processing and presentation?
HCMV US2, US11 and adenovirus E3 gp19 proteins stimulate the MHC to recycle from the cell surface to the cytosol.
why is preventing MHC presentation (by stopping it getting to the surface) not all that good for the virus?
now that the cell lacks MHC it’s gonna get fucked by the Natural Killer cells
how does hCMV stop itself getting fucked by NK cells when it has interfered with MHC presentation?
it makes MHC mimics UL18
what does influenza undergo to escape antigen recognition EVERYTIME?
antigenic drift: mutates and evolves every year
antigen shift: acquires new antigens by reasserting with animal viruses –> pandemics
CMV
US3= binds tapasin and prevents peptides being loaded to MHC.
US6= stops ATP binding to TAP thus preventing translocation.
US36= prevents ATP binding to TAP
HSV ICP47
prevents the loading of peptides in to the transporter protein complex TAP.
adenovirus
revents recruitment of TAP to Tapasin and retains MHC in ER.
EBV
cannot be processed by the proteasome
