17. The immunology of chronic viral infection

Question 1

How does the immune system recognise viruses?

Answer 1

1. The virus is detected and then presented by a dendritic cell
2. The proteins on the virus provide a unique signature that is recognised by the immune system.
3. These peptides are loaded into MHC complexes that can interact with TCRs.

Question 2

How are CD8+ T cells recruited?

Answer 2

1. CD8+ T cells are restricted to MHC class 1.
2. Specific T cells recognise the MHC complex for its specific antigen.
3. Different T cells recognise different antigens.

Question 3

How can specific T cells be identified?

Answer 3

1. Using tetrameric MHC with fluorochrome cores.
2. Make this into a reagent that is specific to the TCR.
3. Then use flow cytometry to identify the phenotype.

Question 4

What causes the immune system to evolve?

Answer 4

Infections that cause selection pressures

Question 5

What is the pattern of acute infection?

Answer 5

1. Become infected
2. may or may not have symptoms
3. Virus cleared by the immune system
4. No detectable virus left
5. The T cell response never goes back to 0 creating immune memory

Question 6

What is lymphocytic choriomeningitis virus? (LCMV)

Answer 6

1. An atypical virus
2. It was used to establish the concept of MHC restriction in 1998.
3. This helped us learn a great deal about the specificity of the response.

Question 7

What was the Armstrong strain of LCMV used for?

Answer 7

1. A strain used to infect mice and prove that a sustained T cell response is produced.
2. Memory T cells so the level never returns to 0.
3. At the peak of infection 50-70% of T cells were responding to the infection.

Question 8

What was learned about infection memory due to LCMV?

Answer 8

1. Cleared viral infection leave populations of central and tissue resident memory cells.
2. Tissue resident memory vastly exceeds the circulating memory.
3. Tissue resident cells are important in limiting reinfection. They remain at the site of infection or places that need extra protection.
4. Tissue resident cells express markers that are also seen on exhausted CD8 T cells.

Question 9

What do tissue resident memory cells do?

Answer 9

1. They adapt to local tissues.
2. Analysis of gene expression that memory cells have varying gene expression based on the tissue they are in.
3. This is due to epigenetic changes and enables them to mediate rapid responses to reinfection.

Question 10

What is a persistent virus with high levels of circulating virus?

Answer 10

HIV

Question 11

What is a persistent virus with low levels of circulating virus?

Answer 11

Herpes

Question 12

what can HIV do?

Answer 12

Have both a low and high viral load which makes it so successful

Question 13

How common is persistent viral infection?

Answer 13

1. very common and it is getting more common.
2. Some other health conditions can be linked to persistent viral infection.
3. Lots of people have persistent viruses and we don’t know the full extent of its healthcare burden.

Question 14

What are the general strategies of viral immune evasion?

Answer 14

1. continuous replication
2. Latency and reactivation
3. genome invasion and vertical transmission

Question 15

What mechanisms do viruses use for evasion?

Answer 15

Viruses are highly adaptive and they can interfere with immune regulation by:
1. decreasing the expression of molecules required for T cell or NK cell recognition.
2. Inhibiting antigen presentation.
3. acting as agonist or antagonists of cytokines and chemokines
4. Blocking intracellular antiviral and proinflammatory effects of interferons and cytokines. (eg IL-10)

Question 16

What are the general strategies for T cell adaptation of the immune response in persistent infection?

Answer 16

1. Inhibitory receptor upregulation
2. Continuous immunosurveillance while minimising immunopathology
3. immunoregulation of soluble mediators
4. Altered APC maturation
5. Regulatory T cells

Question 17

What needs to be in balance during persistent infection?

Answer 17

1. the virus and the immune response
2. When the virus is mostly gone and there is still a strong immune response it causes excess cell damage

Question 18

T cell adaptation to persistent infection: inhibitory receptor up-regulation

Answer 18

1. in some persistent infections the virus is still high and interacts with the immune system.
2. The T cells can become exhausted and start to display different surface receptors.
3. These receptors can inhibit T cell function to prevent the immune system causing excess cell damage.
4. These receptors are CTLA-4, PD-1, LAG-3, 2B4, Tim-3.

Question 19

T cell adaptation to persistent infection: Continuous immunosurveillance while minimising immunopathology

Answer 19

1. Lots of viruses enter latent stages where they can hide from the immune system.
2. Eg herpes entering the trigeminal ganglia.
3. These viruses are still active and can cause a localised immune response.
4. The latent cell is constantly surrounded by immune cells ready to activate should the virus become lytic again.

Question 20

T cell adaptation to persistent infection: immunoregulatory soluble mediators

Answer 20

Adaptive and innate cytokines can help with viral control.
1. type 1 interferons
2. IL-6 and TNF
3. prostaglandins
4. IFN-y from CD8 stimulates the host cell to limit viral replication
5. IL-10 to regulate CD8 populations

Question 21

T cell adaptation to persistent infection: altered APC maturation

Answer 21

As the time infected increases dendritic cells and macrophages downregulate their ability to produce an immune response by reducing MHC1 and other co-stimulatory molecule expression. This makes a smaller immune response causing less damage but could allow the virus to persist

Question 22

T cell adaptation to persistent infection: Regulatory T cells

Answer 22

1. T reg cells decrease the CD8 T cell number and cause a less aggressive immune response.
2. This prevents excess cell damage and preserves the tissue.
3. But it may mean the virus is not cleared

Question 23

What can reactivate a latent virus?

Answer 23

1. We don’t really know so it could be many things.
2. UV light
3. steroids/immunosuppression
4. Fever
5. Stress
6. Transplantation
7. fatigue

Question 24

Where could latent CMV be hiding?

Answer 24

1. in haematopoietic progenitor cells in the bone marrow
2. endothelial cells
3. other cells

Question 25

Reactivation of CMV in bone marrow transplants

Answer 25

1. CMV+ have a 60-70% reactivation rate
2. CMV- have a 20-30% reactivation rate
3. Drugs can be effective prophylaxis
4. Monitoring with PCR is helpful
5. monitoring anti-CMV T cells may be more effective

Question 26

What is the take home message for persistent viral infections?

Answer 26

too much immunity is as bad as not enough