5. Viral evasion of host immunity

Question 1

What are the 2 different aspects of the adaptive immune response?

Answer 1

Cellular (T cells) and humoral (antibodies)

Question 2

Viruses can only survive inside cells, what name is given to these pathogens?

Answer 2

Obligate intracellular pathogens

Question 3

What do viruses tend to conserve well and why is this significant?

Answer 3

• Internal viral proteins for survival
• Can’t vary much for this reason (compared to surface antigens)
• Therefore, they tend to be a target of cellular immunity, and allow us to vaccinate people

Question 4

How does EBV, CMV and HSV prevent MHC 1 transcription to kill the cell occupied by the virus (with reference to TAP)?

Answer 4

• Proteasome chops up the viral peptides
• These peptides are loaded into the endoplasmic reticulum through TAP
• EBV - EBNA1 cannot be cut and processed by proteasome
• HSV - ICP47 blocks access of processed peptide to TAP
• CMV - US6 stops ATP binding to TAP, preventing translocation
• The virus peptide can’t combine with the MHC to be presented
• CD8+ can’t detect the infected cell to kill it

Question 5

What does tapasin do?

Answer 5

• Viral peptide is transferred from TAP to tapasin

* Tapasin places the peptide into the groove of MHC class I molecule, before being transported to the surface

Question 6

How does CMV and adenovirus interact with tapasin to prevent MHC transport?

Answer 6

• CMV - US3 binds tapasin and prevent peptides being loaded to MHC
• Adenovirus - E3-19K prevents the associatation of TAP with tapasin, and retains MHC in the endoplasmic reticulum

Question 7

How does KSHV (Kaposi) evade MHC I presentation?

Answer 7

• kK3 protein covers the MHC with ubiquitin (even if it reaches the surface) and pulls it back = polyubiquitinylation
• MHC is passed from the internalised endosome to the lysosomes

Question 8

Which HPV types cause cervical cancer?

Answer 8

HPV 16 and 18

Question 9

How does HPV evade the immune system?

Answer 9

Proteins E6 and E7 interfere with the innate immune response
• They inhibit TYK2 and IRF9
• This prevents the interferon-alpha signalling pathway
• They also interfere with the cGAS pathway for detecting viral DNA

Protein E5 holds MHC I in the Golgi body and prevents it from migrating to the cell surface - can’t be killed by CD8+

Question 10

What common virus needs to be eliminated from bone marrow cells of a transplant recipient before transplantation and why?

Answer 10

• HCMV
• Problem in immunocompromised/suppressed patients
• Can reactivate and usually seen in first 30 days after transplant

Question 11

What does UL138 in CMV do?

Answer 11

• Protein that leads to a loss of MRP-1
• MRP-1 normally transports toxic substances out of the cell, from the infected cell surface
• Evident in latently infected cells (changes in cell surface)
• Accumulation of certain molecules in infected cell, including the toxic drug vincristine (vinca alkaloid)
• This can treat HCMV before transplantation, by killing the cells

Question 12

Is the cellular or humoral response more important in acute viruses (influenza, rhinovirs, poliovirus)?

Answer 12

Humoral - adaptive response with antibodies

Question 13

Describe how influenza evades the humoral response by antigenic variation?

Answer 13

• Antigenic drift - rapid evolution driven by antigenic pressure from host
• Antigenic shift - introduction of new subtypes from animal source

Question 14

Is there a vaccine for rhinovirus and why?

Answer 14

No, as there are too many subtypes

Question 15

How do pre-existing antibodies for a virus prevent it from infecting?

Answer 15

Sterilising immunity:

Coat the virus before it can latch onto a cell receptor

Question 16

What is haemagglutinin?

Answer 16

• Major influenza viral antigen
• Comprises 2 domains:
- Globular head: stick out of the virus and is detected by antibodies, highly variable
- Stem domain - relatively conserved

Question 17

How does the gp120 protein on HIV resist neutralisation?

Answer 17

• Few gp120 spikes on viral surface
• Large space between spikes - prevents antibody crosslinking
• gp120 is glycosylated - antibody access is hindered
• Functionally important parts (e.g. CD4 binding site) are poorly accessible
• Constantly changing surface amino acids

Question 18

What are bNabs?

Answer 18

• Broadly-neutralising antibodies
• Can latch onto lipids or sugars that make up the viral membrane
• Neutralise different strains for fast evolving viruses e.g. influenza and HIV
• Works really well if given to begin with
• However, escape mutants do appear, in the face of antibodies
- virus can change the more constant region
- viruse did not need this part to survive, it just didn’t need to change this region before

Question 19

What are the 2 vaccines for polio?

Answer 19

• Sabin - live, attenuated vaccine

* Salk - inactivated, dead vaccine

Question 20

Why was administration of all 3 serotypes of poliovirus ineffective for the live attenuated Sabin vaccine?

Answer 20

Resulted in virus interference and poor response to one component - better to give relevant one

Question 21

What happens in Dengue haemorrhagic fever, how can it be detected (in blood test) and how is it treated?

Answer 21

• Leakage of plasma from capillaries
• Tendency to severe bruising and bleeding
• Deterioration after fever => shock
• Increased haematocrit
• Increased red cell count
• Decrease in blood protein

• Treat with IV fluid to hydrate

Question 22

How many Dengue virus serotypes are there?

Answer 22

4

Question 23

When is Dengue virus dangerous and why?

Answer 23

Antibody-dependent enhancement
• Second infection
• When initially infected with one serotype, you develop antibodies against it
• When infected by another serotype, the initial heterotypic antibodies bind but don’t neutralise it
• It can be detected by Fc receptors on immune cells e.g. monocytes
• The complex enters the monocyte (virus normally unable to on its own)
• Replication inside the monocyte
• Monocytes release many IFNs => cytokine storm => DHF

Question 24

What would be needed to make a dengue vaccine?

Answer 24

• Fully neutralising antibodies against all 4 serotypes

* If only 1 serotype was vaccinated against, the person could die from an initial infection

Question 25

How does Ebola evade the antibody response?

Answer 25

• Glycosylated (mucin like) antigens
• Harder for antibodies to neutralise as the glycoproteins are inaccessible in folded pockets
• It has also evolved so there is a soluble version of its glycoprotein (sGP)
• This means the antibodies are mobbed up (bind to sGP, not virus)
• sGP is an antibody decoy, and inhibits neutrophils (immunosuppressive)

Question 26

How can measles cause immunosuppression?

Answer 26

• MV infects CD150+ cells, including memory lymphocytes
• This erases immunological memory
• Leads to morbidity and mortality from other diseases

Question 27

How many measles serotypes are there?

Answer 27

One

Question 28

Are RNA or DNA viruses more likely to have error prone polymerases that promote antigenic variation?

Answer 28

RNA viruses