Immune Evasion by Viruses

Question 1

What is the goal of the immune response in order to overcome a viral infection?

Answer 1

To eliminate both, the virus and the host cells harbouring / replicating the virus

Question 2

How do Abs fight a viral infection?

Answer 2

1. Neutralises extracellular virus: by either blocking viral attachment proteins (e.g., glycoproteins, capsid proteins) or destabilising the viral structure
2. Opsonizes virus for phagocytosis
3. Promotes killing of target cell by the complement cascade and antibody-dependent cellular cytotoxicity
4. Resolves lytic viral infections (viruses that damage host cells, causing them to burst etc.)
5. Blocks viremic spread to target tissue

Question 3

How are the different classes of Abs, IgM, IgG and IgA involved in the immune response against viral infections?

Answer 3

IgM is an indicator of recent or current infection

IgG is a more effective antiviral than IgM

Secretory IgA is important for protecting mucosal surfaces

Question 4

What are the 5 common ways that viruses can use to escape Ab recognition (with examples)?

Answer 4

1. Many different antigenically distinct serotypes (subgroup of a species) - e.g. human rhinovirus
2. Exists as multiple clades (group of microorganisms with a common ancestor)or quasi-species - e.g. HIV Encode secreted surface antigens that mop up the Abs, stopping it reaching virus particles or infected cells - e.g. Hep B virus (HBV) and Ebola virus
3. Antibody dependent enhancement - e.g. the Dengue Virus exists as 4 serotypes. When infected with one serotype, Abs are produced in this primary immune response. Reinfection with a different serotype can lead to mass production of the antibodies produced from the last primary resonse. And so they bind to this virus of a different serotype, forming an Ab–virus complex that attaches to receptors using the Fc region and so enters host cells more efficiently. This triggers Dengue Haemorrhagic Fever.
4. Antigenic drift, when viruses mutate and evolve to change year on year - e.g. Influenza
5. Antigenic shift, can lead to pandemics as viruses can acquire completely new antigens by reassortment with animal viruses - e.g. Influenza

Question 5

What are the consequences of viruses evading Abs medically?

Answer 5

Vaccination programmes for certain viruses cannot be made / introduced e.g. too many serotypes of the rhinovirus and the flu jabs need to be newly made every year

Question 6

What are interferons (IFNs)?

Answer 6

Small proteins produced and released by virally infected cells - used for signalling within the immune response

Question 7

What induces IFN production and what is the role of the IFNs in the immune response?

Answer 7

IFN production and release is induced by the cell when it detects something foreign or unusual, such as double stranded RNA or DNA in the cytoplasm

IFNs bind to IFN receptors, which cause the infected cells to go into the antiviral state - transcription of hundreds of genes that block viral replication e.g. by coding for enzymes

Also activate NK cells and systemic antiviral responses

Question 8

What are the 3 types of IFNs and their properties?

Answer 8

Type I - IFN-α and IFN-β:

IFN-β is secreted by all cells and the IFNαR receptor is present on all tissues

Plasmacytoid dendritic cells (PDCs) are specialist IFN-α secreting cells

There is one gene for IFN-β, but 13/14 isotypes of IFN-α

Type II - IFN-γ:

Produced by activated T cells and NK cells

Signals through a different receptor IFN-γR

Type III - IFN-λ

Signals through receptors IL28R and IL10-β also known as IFN-λ receptors that are mainly present on epithelial surfaces

Question 9

How can viruses evade IFN activity?

Answer 9

Some viruses block the production of IFNs by inhibiting IFN transcription e.g. the Influenza virus produces a protein (NS1) that counters RNA sensing and prevents polyA processing

Question 10

How are NK cells activated and how do they kill enveloped viruses / virally infected cells?

Answer 10

NK cells are activated by IFN-α and interleukin-12, which activate macrophages with IFN-γ

When the NK cell finds a cell displaying fewer than normal MHC molecules (e.g. Cytomegalovirus or Herpes Simplex Virus infected) it releases toxic substances, in a similar way to cytotoxic T cells, which kill the virally-infected cell

Question 11

How do maccrophages and DCs work together to filter viral particles from blood?

Answer 11

Macrophages inactivate opsonised virus particles

Immature and plasmacytoid DCs produce IFN-α and other cytokines

DCs initiate and determine the nature of the CD4 and CD8 T-cell response

DCs and macrophages present antigen to CD4 T cells

Question 12

How do T cells control enveloped and noncytolytic viral infections?

Answer 12

T cells recognize viral peptides presented by MHC molecules on cell surfaces Antigenic viral peptides (linear epitopes) can come from any viral protein (e.g. glycoproteins, nucleoproteins) CD8 cytotoxic T cells respond to viral peptide: class I MHC protein complexes on the infected cell surface CD4 TH2 responses may be detrimental if they prematurely limit the TH1 inflammatory and cytolytic responses

Question 13

What type of viruses (using an example) evade the T cell response and how do they do it?

Answer 13

Usually viruses that result in chronic infections e.g. Herpes simplex HSV and cytomegalovirus CMV They encode proteins that interfere with the MHC antigen processing pathway

Question 14

How does HIV evade the immune response (specifically T cells)?

Answer 14

They infect and kill CD4 T cells and alter macrophage function

Question 15

Summary of Viral Evasion strategies:

Answer 15

1. Modulate surface structure to avoid recognition i.e. antigenic variability
2. Block IFN transcription, so IFNs aren’t produced to further signal the immune response
3. Secrete surface antigens that mop up antibodies
4. Many serotypes / clades
5. Infect cells of the immune response
6. Interfere with MHC antigen processing pathway to prevent activation of further immune responses