4. Viral evasion of host immunity

Question 1

What are viruses and how are they presented?

What is the role of cellular immunity and what can be a target of this?

Give an example of an evading virus

Answer 1

Viruses – intracellular pathogens:

• o Represented via MHC I mechanisms.
• o Cellular immunity clears viral infection but is short-lived
• o Internal viral proteins can be targets of cellular immunity as they vary less than surface antigens.
• o Evading virus example – Herpes Simplex Virus (evades cellular immunity)

Question 2

Describe the process of presentation of viral peptides on MHC I

Answer 2

Presentation of viral peptides on MHC class I

• 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/processed by the proteasome

HSV – ICP47 – blocks access of the processed peptides to the TAP protein

CMV – US6 – blocks ATP binding to TAP thus 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

NOTE: tapasin is involved in loading MHC molecules

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 internalised 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?

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

Answer 6

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

Viruses which evade this mechanism:

– Viruses encode MHC analogues (e.g. CMV gpUL40) OR upregulate MHC

virally encoded MHC is useless but it fools the NK cells

Question 7

What is the result of destruction of T-cells and give examples of drugs which do this?

Answer 7

Destruction of T cells leads to Virus Pathology

- 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 8

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

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

Answer 8

Immunocompromised

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

Question 9

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

Answer 9

• 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 10

What can antigenic variation occur due to?

Answer 10

• o Continued rapid evolution is driven by antigenic pressure from the host.
• o Introduction of new subtypes from animal sources.
• o Existing as different stable serotypes that co-circulate in humans.
• o Consequence of vaccination.

Question 11

What is antigenic drift vs. shift?

Answer 11

Drift:

• Continued rapid evolution, driven by antigenic pressure from the host

Shift:

• 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 12

Why is it difficult to make a vaccine for human rhinoviruses?

Answer 12

• Human rhinovirus antigenic variation*
• -* Human rhinoviruses cause the common cold
• They exist as more than 120 antigenically distinct serotypes that co-circulate
• It is impossible to make a vaccine against all of them

Question 13

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

Answer 13

3 – trivalent vaccine
NOTE: one of the serotypes has been eradicated now

Question 14

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

What is the treatment?

Answer 14

Leakage of plasma from capillaries leads to, this loss of fluid from the blood leads to:

• Increased haematocrit
• Increased red cell count
• Decrease in protein
• Tendency to severe bruising and bleeding

Treatment: treat with IV fluids

Question 15

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

Answer 15

4 serotypes of dengue

• 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 16

How do viruses such as HIV and ebola evade the antibody response?

Answer 16

Heavily glycosylated glycoprotein antigens

• Some viruses have glycoprotein antigens that are so heavily glycosylated that antibody access is hindered e.g. HIV and ebola
• It can be so heavily glycosylated that it looks more like human mucin than viral antigens

Question 17

What other features of ebola allow it to be evaded from the antibody response?

Answer 17

High content of phosphatidyl serine lipids

• Ebola virus particle membranes have a high content of phosphatidyl serine lipids making them look like apoptotic bodies
• As they look like apoptotic bodies, they are rapidly taken up by macropinocytosis, away from antibody surveillance (antibodies can only help to neutralise viruses outside cells)

Long filamentous shape

• Ebola also has a long filamentous shape, which has lots of folds so the glycoproteins may be inaccessible in these viral pockets making it harder for antibodies to neutralise the glycoprotein

Question 18

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

Answer 18

VP35
VP24

Question 19

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

Which virus is only suppressive in macaques?

Answer 19

Ebola synthesises soluble glycoprotein – this acts as an antibody decoy and it is immunosuppressive (inhibits neutrophils)

• • Soluble glycoprotein is the default coding for the glycoprotein (GP) gene*
• • Full length GP is made by polymerase stuttering*
• • NOTE: GP2 and retrovirus glycoproteins also have an immunosuppressive peptide*

- Reston virus version is only suppressive in macaques

Question 20

How does Measles infect cells?

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

Answer 20

Measles infect cells via SLAM proteins (CD150)

• Measles infect CD150 (SLAM) positive cells, which includes 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 other diseases

Question 21

SBA: Which answer is not true?
Viruses that can’t control the innate immune system well might….

A: be useful as oncolytic agents

B: be difficult to grow in standard cell culture systems

C: be restricted at crossing the host range barrier and unlikely to spark outbreaks in other species

D: be useful as live-attenuated vaccines

E: be highly adapted to their host species

Answer 21

E: be highly adapted to their host species

Question 22

SBA: Which is true?
Viruses counteract the activation of the interferon system by:

A: varying their coat protein sequences

B: encoding proteins that cleave or target host factors for degradation

C: preventing the loading of peptides by TAP

D: inducing a cytokine storm

E: encoding MHC homologues

Answer 22

B: encoding proteins that cleave or target host factors for degradation

Question 23

SBA: Which is true?
RNA viruses are more likely than DNA viruses to

A: code for proteins that interfere with innate immunity

B: code for proteins that interfere with cellular immunity

C: Have error prone polymerases that promote antigenic variation

D: Use lipid envelopes to protect their genomes that also contain host proteins that control complement activation

E: Activate interferon induction pathway through cGAS and STING.

Answer 23

C: Have error prone polymerases that promote antigenic variation

Question 24

SBA: Which is NOT true concerning the interplay between
Hepatitis C virus and the immune systems

A: Its E2 protein varies by more than 30% so antibodies only bind a tiny fraction of the viral quasispecies

B: T cell epitopes vary so that the virus is not cleared in the early stage of infection and this determines chronicity

C: NS3/4A protease cleaves MAVS and prevents activation of interferon

D: It encodes a protein called vif that counteracts the interferon stimulated gene APOBEC and prevent it from inducing hypermutation of the viral genome

E: A genetic polymorphism in IL28b results in non-responsivenes to interferon treatment

Answer 24

D: It encodes a protein called vif that counteracts the interferon stimulated gene APOBEC and prevent it from inducing hypermutation of the viral genome