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

It will then move to golgi apparatus

Finally it is moved 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, therefore preventing translocation

Question 4

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

Answer 4

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

From the internalized endosome, MHC is passed 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

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

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

What is antigenic drift?

Answer 12

Continued rapid evolution driven by antigenic pressure from the host

Question 13

What is antigenic shift?

Answer 13

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 14

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

Answer 14

They can have several genetically stable serotypes that co-circulate

E.g. rhinovirus has more than 120 antigenically distinct serotypes

Question 15

How many serotypes of influenza are there?

Answer 15

4

Question 16

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

Answer 16

3 – trivalent vaccine

NOTE: one of the serotypes has been eradicated now

Question 17

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

Answer 17

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

Question 18

What is the treatment for DHF?

Answer 18

IV fluids

Question 19

How many serotypes of dengue are there?

Answer 19

4

Question 20

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

Answer 20

ANTIBODY DEPENDENT ENHANCEMENT: Antibody generated against a previous infection (different serotype) can bind to the new serotype but not neutralize the virus. Fc receptors on monocytes can then bind to the Ab (bound to antigen). After ingesting this, the virus can now replicate inside the monocyte. This leads to mass release of cytokines by monocytes (cytokine storm), causing Dengue Haemorrhagic Fever.

Question 21

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

Answer 21

Heavily glycosylate the antigens

Question 22

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

Answer 22

Phosphatidyl serine lipids

Question 23

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

Answer 23

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

Question 24

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

Answer 24

Ebola has a long filamentous shape with lots of folds

The folds may make the glycoproteins inaccessible to antibody

Question 25

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

Answer 25

VP35

VP24

Question 26

How does vaccination against measles protect us from other infections?

Answer 26

1. MV infects CD150 (aka SLAM) positive cells, this is presented on memory lymphocytes and erases immunological memory.
2. This results in a 2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.

3.Vaccination against measles therefore prevents loss of immunological memory and so you are less likely to suffer from other infections. Therefore a measles vaccine protects you from a lot of other infections on top of the measles itself.

Question 27

What is tapasin?

Answer 27

Protein involved in loading protein fragments brought into the ER by TAP onto the MHC molecule.

Question 28

How does HPV counter the immune response?

Answer 28

Encodes proteins:
E5 - prevents MHC-I and MHC-II from reaching the cell membrane (adaptive)

E6 and E7 - block interferon production (innate)

Question 29

What is the major influenza viral antigen?

Answer 29

Haemagglutinin

Question 30

What are the features of the major influenza viral antigen (haemagglutinin)

Answer 30

globular Head region is highly variable

Stalk is highly conserved

Question 31

What was the initial problem with the sabin vaccine?

Answer 31

Administration of all 3 viruses at once lead to 2 of the stronger serotypes out competing a weaker serotype

Resulted in good antibody production against 2 serotypes and poor antibody production against the other 1

Question 32

How does HIV evade antibodies?

Answer 32

Large space between spikes prevents Ab crosslinking

Extensive glycosylation masks antibody epitopes

Functionally important parts of the molecule are poorly accessible - redundant amino acids are visible to B cell receptor and antibodies.

Huge variation in the redundant amino acids means most antibodies are highly clade specific.

Question 33

What are the theories for why HIV stalk is well conserved and which is most likley?

Answer 33

1. Stalk is conserved because it is vital for HIV’s activity
2. Conserved because there is no selection pressure - less antibodies produced against it because its harder to access.
   This is more likely - antibodies have been produced against the stalk but escape mutant appear