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

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

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

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

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

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

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

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 changing their 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

Question 17

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

Answer 17

3 – trivalent vaccine

NOTE: one of the serotypes has been eradicated now

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

Question 19

What is the treatment for DHF?

Answer 19

IV fluids

Question 20

How many serotypes of dengue are there?

Answer 20

4

Question 21

Explain the significance of the presence of multiple serotypes of dengue 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 Fever

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

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

Via SLAM proteins (CD150)

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

Give some reasons as to why antigenic variation occurs?

Answer 31

1. Continued rapid evolution driven by antigenic pressure from host e.g influenza antigenic drift, HIV quasispecies
2. Introduction of new subtypes from animal sources e.g antigenic shift
3. Existing as different stable serotypes that co-circulate in humans e.g human rhinovirus has 120
4. Consequence of vaccination

Question 32

How does the HIV envelope glycoprotein 120 resist neutralisation?

Answer 32

1. Large space between spikes preventing antibody cross linking
2. Extensive glycosylation masks antibody epitopes
3. Functionally important parts of antigen are poorly accessible- CD4 binding site

Question 33

What are BNabs are what is their relevance in viruses like influenza and HIV?

Answer 33

they are broadly neutralising antibodies

• controls viral load but mutants do appear over time of use individually
• make antibody against the hemagglutinin 2 region (conserved region) theoretically could be immune against influenza as only variable region mutates