Adaptive immunity against viruses and viral evasion strategies

Question 1

What is adaptive immunity to viruses?

Answer 1

The humoral response - Abs prod by B lymphocytes
The cellular response mediated by T-lymphocytes

Question 2

Describe the humoral response to viruses

Answer 2

Effective at clearing cell-free viruses
Both neutralising and non-neutralising Abs can be important

Question 3

Describe the cellular response to viruses

Answer 3

Effective at clearing cell-associated viruses

Question 4

What do antibodies do?

Answer 4

Neutralisation - prevents receptor binding
Opsonisation - promotes phagocytosis
Complement activation - activate complement which enhances opsonisation

Question 5

What viral proteins can be present on infected cells?

Answer 5

Haemagglutinin
Neuraminidase
M2

Question 6

How do antibodies clear and neutralise non-enveloped viruses?

Answer 6

At fewer than 2 IgG molecules per virus BUT virus particles have hundreds of identical subunits so 1 or 2 IgG molecules per virion would not prevent receptor recognition or opsonise the virion so Abs mediate intracellular immunity through TRIM21

Question 7

What is TRIM21?

Answer 7

A cytosolic ubiquitin ligase and high affinity IgG receptor
Detects antibody-coated viruses or bacteria that have entered the cytosol

Question 8

Describe what TRIM21 does

Answer 8

Responsible for antibody-dependent intracellular neutralisation (ADIN)
Detects Ab-bound substrates inside the cell and mediates rapid proteasomal degradation of those substrates
When targeting a virion, this blocks infection

Question 9

Describe the mechanism by which TRIM21 works to block infection

Answer 9

Viruses that enter the cytosol and traffic surface-bound Abs into the cell recruit TRIM21 via high affinity interaction between Fc and TRIM21 PRYSPRY domain
This triggers a coordinated effector and signalling response that prevents viral replication
Auto-ubiquitination of TRIM21 targets the viral components to the proteasome, neutralising the infection

Question 10

Describe the structure of TRIM21

Answer 10

Fc-binding PRYSPRY domain
Coiled coil dimerisation domain
B-box domain
N-terminal RING domain with E3 ubiquitin ligase activity

Question 11

How does TRIM21 have clinical relevance?

Answer 11

In systemic lupus erythematosus
Autoantibodies against RING and B-box domain of TRIM21 generated

Question 12

How do CD8+ T cells cause lysis of target cells?

Answer 12

They either release cytotoxic granules at the site of contact with the target cell (must be directed to prevent damage to innocent bystander cells)
Or engage Fas/FasL interaction

Question 13

What causes lysis by cytolytic CD4+ cells during infection?

Answer 13

Upregulation of MHC-II
e.g. WNDV-infected MHC-II positive epithelial cells, EBV-infected B cells, HIV-infected CD4+ cells

Question 14

How do CD4+ T cells kill viruses that replication in macrophages?

Answer 14

Interacting Th1 cells secrete IFN-g
Triggers intracellular membrane fusion and ROI/NO killing of pathogens

Question 15

What is required for control of acute viral infections?

Answer 15

Th1 and Tfh subsets of CD4+ cells

Question 16

Describe the development of CD4+ subsets

Answer 16

Pathogen interacts with APC and detected by PAMPs
Ags presented on surface
Naive CD4+ cell activated and IL-2 released
Causes expansion of CD4+ clone
Th1 subset differentiated by release of IL-12 from APC

Question 17

What do Th1 cells do?

Answer 17

Promote CD8+ expansion and activation and B cell maturation

Question 18

What cytokines are produced by viral infection of DCs and macrophages?

Answer 18

Type 1 interferon - IFN-a, IFN-b
IL-12
IL-15
Type 2 interferon - IFN-g

Question 19

What cells produce type 1 ifn?

Answer 19

DCs
Macrophages
Epithelial fibroblasts

Question 20

What cells release IL-12?

Answer 20

DCs
Macrophages
Also prod by CD4+ engagement of DCs

Question 21

What cells produce IL-15?

Answer 21

Macrophages

Question 22

What cells produce type 2 ifn?

Answer 22

Macrophages

Question 23

What are the 2 components of antibody memory?

Answer 23

Long-lived plasma cells secrete Ig of high specificity in absence of continued antigen
Memory B cells divide very slowly to maintain specific population also in absence of Ag but can be rapidly expanded in presence of Ag

Question 24

What happens to mature T cells if not stimulated?

Answer 24

Undergo apoptosis

Question 25

How long do memory T cells live?

Answer 25

Months (not as long as memory B cells)

Question 26

What do memory T cells express?

Answer 26

Survival factors such as Bcl2, Bcl-XL

Question 27

What stimulates memory T cell division?

Answer 27

IL-7 and IL-15

Question 28

What drives expansion of memory T cells?

Answer 28

Either DCs or macrophages

Question 29

What has central memory?

Answer 29

Lymph nodes
Poor effectors but generate effector cells when challenged

Question 30

What does virus latency reduce?

Answer 30

Antigen expression
e.g. EBV, CMV and chickenpox all establish latent infections and only express 5-10 antigens during these infections

Question 31

What is the difference in antigenic variation in acute vs chronic infections?

Answer 31

Acute infectious viruses e.g. flu generate antigenic variants but these are not necessary for the course of infection and is not a survival strategy for an ongoing infection
However in chronic viral infections e.g. HCV and HIV, antigenic variation is a necessary part of the infection

Question 32

What are active mechanisms of evading adaptive immunity?

Answer 32

Viral IgG Fc receptors
- Binding of IgG and inhibition of Fc-dependent immune activation
e.g. Varicella Zoster, CMV

Question 33

What are active mechanisms of evading adaptive immunity?

Answer 33

Viral IgG Fc receptors
- Glycoproteins of viruses act as distractor receptors for IgG, preventing ADCC and phagocytosis of infected cells
e.g. Varicella Zoster, CMV

Question 34

How do viruses block cytokine secretion?

Answer 34

Homologues of cellular cytokine receptors produced by virus (secreted versions of cellular cytokine receptors lacking transmembrane and cytoplasmic domains)
Act as decoy receptors and bind chemokines/cytokines with high affinity and block their activity