Viral Evasion of the Host Immune Response

Question 1

What is a key difference between internal virus proteins and surface antigens?

Answer 1

Internal viral proteins vary less

Viruses are intracellular pathogens 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 for cellular immunity - as they are

intracellular, they tend to vary LESS than the surface antigens

Viruses that persist must evade cellular immunity

Question 2

Describe the process of presentation of viral peptides on MHC Class I.

Answer 2

Viral peptides 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 it will then move to the cell surface where T cells can recognise the antigen.

Foreign peptides inside the cell (e.g. viral peptides) will be chopped up into smaller peptides inside the proteasome

They then get fed in through the TAP protein into the endoplasmic reticulum where it gets loaded onto an MHC class I molecule

This loaded MHC then moves to the cell membrane where the viral peptide can be recognised by T cell receptors on the surface of cytotoxic T cells

The T cell can then kill the virus infected cell

Viruses that persist must be able to suppress this system

Question 3

State three viruses (and the proteins involved) that evade antigen loading onto TAP.

Answer 3

EBV – EBNA1 – this cannot be chopped up by the proteasome HSV – ICP47 – blocks access of the peptides to the TAP protein CMV – US6 – blocks ATP binding to TAP

RECAP: the proteasome chops up the viral peptides and loads them into the endoplasmic reticulum through TAP (transporting molecule)

EBV expresses a protein called EBNA1 that CANNOT be cut up into smaller peptides in the proteasome - so EBV can exist in the cell but its proteins are not processed

HSV encodes ICP47, which blocks access of the processed peptide to TAP

CMV encodes US6 which stops ATP binding to TAP, which is required for TAP to

be able to transport peptides across the membrane

Question 4

State two viruses (and the proteins involved) that modulate tapasin function and prevent MHC transport.

Answer 4

NOTE: tapasin is involved in loading MHC molecules Adenovirus E3-19K – prevents recruitment of TAP to tapasin and retains MHC in the ER CMV – US3 – binds to tapasin and prevents loading of peptides onto MHC

CMV encodes US3, which binds to tapasin and prevents peptides being loaded onto MHC

Adenovirus E3-19K prevents recruitment of TAP to tapasin and also retains MHC in the ER

Question 5

State one virus (and the protein involved) that interferes with MHC presentation at the cell surface.

Answer 5

KSHV (Kaposi Sarcoma Herpes Virus) – kK3 – induces polyubiquitination and internalisation of MHC

Kaposi Sarcoma Herpes Virus (KSHV) kK3 protein induces polyubiquitination and internalisation of MHC

If MHC isn’t present on the cell surface then the virus peptides wont be presented to T cells

From the internalised endosome, MHC is passed on to lysosomes where it is degraded

Question 6

What do NK cells recognise on the cell surface that triggers killing of cells?

Answer 6

Missing self – lack of MHC on the cell membrane is not healthy

How viruses avoid NK killing by the missing-self mechanism

Normal, healthy cells all display MHC on their cell membrane

Cells that do NOT display MHC are detected by NK cells and killed

This means that viruses that disrupt MHC presentation would end up being

killed by NK cells

To avoid this, viruses encode MHC analogues (e.g. CMV gp UL40) or upregulate

MHC

The virally encoded MHC is useless and does NOT trigger the immune response but it does fool the NK cells into thinking that the cells are normal

Question 7

How do viruses evade this mechanism of NK-mediated killing infected cells?

Answer 7

Viruses encode MHC analogues (e.g. CMV gp UL40) – virally encoded MHC is useless but it fools the NK cells Upregulate MHC

Question 8

Which cells does HIV target?

Answer 8

CD4+ T cells

HIV targets CD4+ T cells and depletes the ability to support an immune

response

Ebola virus infection also results in the destruction of target dendritic cells and

macrophages by direct infection and of T cells by a bystander response

Question 9

Which cells does Ebola kill?

Answer 9

Dendritic cells Macrophages T cells (by the bystander response)

Question 10

In what subset of the population does HMCV (human cytomegalovirus) cause disease?

Answer 10

Immunocompromised

Question 11

What is the problem with HCMV with regards to bone marrow transplantation?

Answer 11

HCMV infects 60-90% of the population If HCMV is present in donated bone marrow, it could cause problems in the immunocompromised recipient

Question 12

Explain how our knowledge about HCMV has allowed improved medical outcomes in bone marrow transplantation.

Answer 12

HCMV encodes UL138, which leads to loss of MRP-1 from the infected cell surface MRP-1 is a transporter of toxic drugs out of the cell Loss of MRP-1 leads to accumulation of certain molecules in the infected cell Vincristine is a toxic drug that accumulates in the infected cells and kills them So treating donated cells with vincristine before the transplant can eliminate CMV

Question 13

What is antigenic drift?

Answer 13

Continued rapid evolution driven by antigenic pressure from the host

Question 14

What is antigenic shift?

Answer 14

Introduction of new subtypes of the virus from an animal source NOTE: when they come from an animal source, the antigens don’t look like anything that humans have seen before

Question 15

How else can viruses cause regular infections without changingtheir antigen profile?

Answer 15

They can have several genetically stable serotypes that co-circulate E.g. rhinovirus has more than 120 antigenically distinct serotypes

Question 16

How many serotypes of influenza are there?

Answer 16

4

Influenza exists as FOUR different serotypes that are drifting year on year

WHO tries to predict which influenza serotype is most likely to cause flu in the

next year before deciding on the next vaccine

There is a lot of interest in developing a universal flu vaccine - there are

attempts to produce antibodies against the parts of the spike proteins that are conserved

Question 17

How many serotypes of poliovirus are there and what type of vaccine was produced for polio?

Answer 17

There are THREE serotypes of poliovirus

This required a TRIVALENT POLIO VACCINE

One serotype has been eliminated from the world

Question 18

What are the features of dengue haemorrhagic fever (DHF)?

Answer 18

Leakage of plasma from capillaries leads to: Increased haematocrit Increased red cell count Decrease in protein Tendency to severe bruising and bleeding

Consequences of Antigenic Variation in Dengue Virus

Dengue haemorrhagic fever (DHF) is responsible for a lot of hospitalisation and fatalities each year

It causes leakage of plasma from the capillaries

The loss of fluid from the blood leads to an increased haematocrit and increased red cell count and a decrease in protein in the blood

Tendency to severe bruising and bleeding

Patient deteriorates even after the fever drops: shock

Treat with IV fluids

Question 19

What is the treatment for DHF?

Answer 19

IV fluids

Question 20

How many serotypes of dengue are there?

Answer 20

Dengue exists as FOUR serotypes

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

In other words, 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 neutralise the new serotype of dengue and it will cause antibody dependent enhancement of the current dengue serotype causing dengue haemorrhagic fever

Question 21

Explain the significance of the presence of multiple serotypes ofdengue with regards to the pathogenesis of DHF.

Answer 21

Infection with one serotype will cause antibody production Antibody generated against this serotype will bind to but NOT neutralise infection with another dengue serotype This can lead to ANTIGEN DEPENDENT ENHANCEMENT (ADE) causing Dengue Haemorrhagic Feve

Question 22

What can viruses do to glycoprotein antigens that hinder antibody access to the antigens?

Answer 22

Heavily glycosylate the antigens

Question 23

What does Ebola viruse have a high content of that makes them appear like apoptotic bodies?

Answer 23

Phosphatidyl serine lipids

Question 24

What is the benefit to Ebola virus of appearing like apoptotic bodies?

Answer 24

They are rapidly taken up by macropinocytosis and, hence, taken away from antibody surveillance

Question 25

How does the structure of Ebola affect antibody access to antigens?

Answer 25

Ebola has a long filamentous shape with lots of folds The folds may make the glycoproteins inaccessible to antibody

Question 26

Name two factors produced by Ebola that allow it to evade detection by the innate immune system.

Answer 26

VP35 VP24

RECAP from interferon lecture: VP35 and VP24 stop the innate immune system from seeing ebola

Ebola pretends to be an apoptotic body so it gets rapidly taken up by cells and doesn’t hang around outside where it could get detected by antibodies

Ebola also synthesises soluble glycoproteins that act as an ANTIBODY DECOY

Soluble glycoprotein is the default coding for the glycoprotein (GP) gene

Full length GP is made by polymerase stuttering

Other than being an antibody decoy, soluble glycoprotein is also

immunosuppressive and inhibits neutrophils

GP2 and retrovirus glycoproteins have an immunosuppressive peptide

Reston virus version is only suppressive in macaques

Question 27

What important factor does Ebola encode that also helps deal with the antibody response?

Answer 27

Soluble glycoprotein – this acts as an antibody decoy and it is immunosuppressive (inhibits neutrophils) NOTE: GP2 and retrovirus glycoproteins also have an immunosuppressive peptide

Question 28

Which virus is only suppressive in macaques?

Answer 28

Reston virus

Question 29

How does Measles infect cells?

Answer 29

MEASLES vaccination had a much larger impact on childhood mortality than

expected

Measles infects CD150 (SLAM) positive cells, which includes memory

lymphocytes and ERASES IMMUNOLOGICAL MEMORY

So a measles virus infection can result in a 2-3 year decrease in immunological

memory that leads to morbidity and mortality from other diseases

Question 30

Why did the measles vaccine have a much larger effect on childhood mortality than expected?

Answer 30

Measles can infect memory lymphocytes (these are SLAM positive) and erase immunological memory So a measles virus infection can result in a 2-3 year decrease in immunological memory that leads to morbidity and mortality from otherdiseases

Question 31

Answer 31

E - viruses that are adapted to the host species are likely to be able to control their innate immune response

Question 32

Answer 32

B - e.g. signalling molecules in the innate immune system

Question 33

Answer 33

3. C

Question 34

Answer 34

4. D - HIV encodes Vif, which counteracts IFN