18 - Viral Evasion of Adaptive Immunity

Question 1

Cells of adaptive immune response

Answer 1

• CD4 Th cell
• CD8 CTL
• B cell
• Antibody

Question 2

B cells

Answer 2

Synthesise antibodies which are responsible for humoral immunity

Question 3

T cells

Answer 3

Mediate cellular immunity and ‘help’ B cells to produce antibodies

Question 4

Antigen presentation by APCs

Answer 4

• After a virion is ingested by an APC, it is degraded in a phagolysosome
• After degradation, the virion’s proteins have been broken down to 9-25 amino
  acids long
• Some of these peptides are subsequently loaded into the cleft of MHC-II molecules, and are then transported to the cell surface

Question 5

Viral evasion of MHC-II

Answer 5

• Reduction of transcription of MHC-II genes
• Degradation of MHC-II proteins in the ER
• Targeting the MHC-II from golgi body to lysosomes where the MHC-II will be degraded
• Blocking processed epitopes from reaching MHC-II containing secretory vesicles

Question 6

TCR

Answer 6

• Dimer of polypeptides α and TCR β chains
• A variable region at the distal portion of the TCR is the site for epitope binding

Question 7

BCR

Answer 7

• Transmembrane form of the antibodies secreted by activated B cell
• When an activated TH cell interacts with a B cell, the viral peptide is presented to the CD4+ T cell TCR in the
  context of MHC-II
• If the TH cell recognizes that epitope, the B cell will proliferate and its offspring will differentiate into
  antibody-producing plasma cells and memory cells

Question 8

What do B cells differentiate to produce

Answer 8

High affinity virus specific antibodies

Question 9

BCR expressions of virion

Answer 9

• When the BCR binds to an epitope on the surface of a virus, the B cell internalizes the virus
• The B cell degrades the virus and ultimately the same epitope that allowed the BCR to bind to the virus in the first place is displayed in MHC-II molecules on the surface of the B cell.

Question 10

How do antibodies help control a viral infection

Answer 10

• Neutralisation: Antibody binds to virion, the antibodies physically prevent the virion from approaching its receptor
• Opsonisation: Professional APCs use a cellular receptor that binds to the constant region of the antibodies to initiate phagocytosis and destroy a virus

Question 11

IgA

Answer 11

• Critical for antiviral defense at mucosal surfaces
• Polymeric IgA is a dimer joined at its Fc ends
• Undergoes transcytosis to be effective (movement to surface of epithelial cells)

Question 12

Viral evasion of neutralising antibodies

Answer 12

Viruses can spread from one cell into another without spending much time in the extracellular space cannot be neutralised by antibodies

Question 13

Mechanism of spread by viruses

Answer 13

• Release of completely assembled viral particles to extracellular environment
• Formation of syncytia
• Intracellular extensions that connect two distant cells to facilitate transport of viral components (requires F actin polymerisation) e.g. RSV
• Intracellular pores that connect two adjacent cells, allowing flow of viral components. e.g. measles

Question 14

Formation of syncytia

Answer 14

• Involves the fusion of infected cells with adjacent target cells and remains an important mechanism of direct cell to cell spread of viral components.
• e.g. HIV

Question 15

Glycosylation

Answer 15

Can mask epitopes on viral spike proteins to prevent antibody binding

Question 16

CD8

Answer 16

Bind MHC-1

Question 17

CD4

Answer 17

Binds MHC-2

Question 18

Viral evasion of CTL response

Answer 18

• An abundant viral protein to be resistant to degradation by the proteasome
• To prevent transport of peptides from the proteasome into the ER through TAP
• To target vesicles containing MHC-I–epitope complexes to the lysosome so that the complexes get degraded and
  never reach the plasma membrane
• To prevent the MHC-I–epitope complexes from leaving the Golgi apparatus so that they never reach the plasma membrane

Question 19

NK cell targets

Answer 19

• Normal cell has high levels of MHC-1 peptide complexes on its surface, so that the NK cell does not attack
• NK cells detect an abnormal cell with reduced levels of MHC-1 peptide displayed and will subsequently kill the cell

Question 20

Complemented stimulated by antibodies

Answer 20

• A cell infected by an enveloped virus has virus spikes on the surface of its plasma membrane.
• Antibodies that bind to these spike proteins stimulate the complement system so that the MAC (membrane attack complex) forms on the infected cell.
• The infected cell dies before viral replication is complete

Question 21

VIral evasion of complement response

Answer 21

• Influenza virus: the M1 viral matrix protein prevents the first complement activation step from occurring.
• Herpes simplex virus I and smallpox virus make proteins that interfere with the third step.
• In all of these evasion strategies, MAC formation is prevented

Question 22

IL-10

Answer 22

• One of the functions of IL-10 is to suppress immune cell activity at the end of an infection
• Herpesviruses stimulate host cells to secrete IL-10, and others encode viral proteins that mimic IL-10, which both suppress the activation of CTLs.

Question 23

Absence of Il-10

Answer 23

• Via genetic deficiency, antibody treatment, weak induction by pathogen
• Leads to severe immunopathology and increased level of apoptosis

Question 24

EBV latent infection

Answer 24

• EBV nuclear antigen (EBNA) 1 protein binds to viral DNA and allows the EBV genome to be maintained in the B cell as a circular DNA episome
• EBV LMP-2 prevents reactivation of EBV from latently infected cells by blocking tyrosine kinase phosphorylation, and allows nontransformed B cells to
  survive

Question 25

EBNA 1 and LMP2A

Answer 25

• The proteasome is unable to degrade EBNA1, so that EBNA1 epitopes are never loaded into MHC-I.
• LMP2A can be degraded by the proteasome, but its epitopes are subdominant to cellular peptides and are rarely selected for display

Question 26

Adaptive immune response to IAV

Answer 26

• Anti-IAV antibodies bind to HA neutralize and opsonize
  the virions, increasing phagocytosis and destruction of the virions
• Anti-IAV antibodies bind to NA and inhibit its ability to degrade the sialic acid component of mucus, trapping the viruses in the mucus
• Anti-IAV antibodies bind to spike proteins on the surface of infected cells and direct the complement to form a MAC on the infected cell, which lyses it
• Anti-IAV CTLs detect viral antigens presented by MHC-I and trigger infected cells to undergo apoptosis before the virus completes its replication cycle

Question 27

Examples of viruses that produce a rash or lesion over extensive areas of the body, even though the primary infection began at a distant mucosal surface

Answer 27

• Measles
• Smallpox
• Varicella Zoster virus

Question 28

How do viruses cause rashes or lesions

Answer 28

• Results when the primary infection escapes the local defenses and virus particles or infected cells spread in circulatory system to initiate foci of infected cells in skin
• Th1 cells and macrophages activated by the initial infection home to these secondary sites and respond by aggressive synthesis of cytokines, including IL-2 and IFN-γ.
• Such cytokines then act locally to increase capillary permeability

Question 29

Naive / activated lymphocytes

Answer 29

• Naive cells are already specialized in that they express many copies of a single TCR or BCR, but they have never been exposed to an antigen that could activate them.
• Activated lymphocytes have been exposed to an epitope that matches their TCR or BCR and have enhanced activities such as killing infected cells or secreting antibodies