Viral infections: Viral Evasion

Question 1

Virus regulation

Answer 1

Virus Regulation

• Viruses – intracellular pathogens:
  
  • Represented via MHC I mechanisms.
  • Cellular immunity clears viral infection but is short-lived.
  • Internal viral proteins can be targets of cellular immunity as they vary less than surface antigens.
  • Evading virus example – Herpes Simplex Virus.

Question 2

Discuss viral evasion mechanisms

Answer 2

Virus Evasion – MHC Evasion:

Some viruses evade MHC class 1 antigen presentation

Evasion of Antigen Loading to TAP:

• EBV EBNA1 cannot be processed by the proteasome (glucine rich structure cannot be picked up and it’s invisible to the cell)
• HSV ICP47 blocks access of processed peptide to TAP.
• CMV US6 stops ATP binding to TAP thus preventing translocation.

Modulation of Tapasin Function and Prevention of MHC Transport:

• CMV US3 binds Tapasin and prevents peptides being loaded to MHC.
• Adenovirus E3-19K prevents recruitment of TAP to Tapasin and retains MHC in ER.

Interfering with MHC Presentation at Cell Surface:

• KSHV kK3 protein induces polyubiquitinylation and internalisation of MHC.
  
  • From internalised endosome, MHC is passed to lysosomes -> recycling of MHC which is never presented
  • Kaposi’s Sarcoma (connected to HIV virus in immunosuppressed people)
• Human papillomavirus counters the innate immune response and the cellular immune response (has E5 protein that blocks MHC 1 molecule from being presented)

PROBLEM ARISING: cells without MCH survive T-cells but are killed by NK cells

– NK Killing Evasion:

• Normal healthy cells display MHC at the surface, cells that don’t display MHC are detected by NK cells and killed.
• Viruses that disrupt MHC presentation would end up being killed by NK cells.
• Viruses can encode MHC analogs (CMV gpUL40) or upregulate MHC
  
  • Human cytomegalovirus - keeping itself in balance by stocking some proteins

Question 3

Virus evasion

Question 4

Explain the significance of the measles vaccine

Answer 4

Measles – Erase Immunological Memory:

• Measles vaccination had a much larger impact on childhood mortality than expected (>90% reduction in death).
• Measles infects CD150+ cells (SLAM), including memory lymphocytes and erases the immunological memory.
• So, a measles infection can result in a 2-3 year decrease in immunological memory that leads to morbidity and mortality from other diseases.

Question 5

Discuss antigenic variation with relevant examples

Answer 5

Antigenic Variation

Antigenic variation occurs due to:

• Continued rapid evolution driven by antigenic pressure from host.
• B-cells produced antibodies cannot bind and neutralize antigens because they constantly change

Examples include – influenza antigenic drift, HIV quasispecies (many versions resulting from replication)

• Antigenic drift is the change of the antigens on a virus picked up from an infected cell that give it immunity to antibodies formed against its old self.
• This means the influenza vaccine must be updated year-on-year.
• The seasonal flu vaccine can be trivalent or quadrivalent depending on how many strains of influenza are about – i.e. pH1N1, H3N2, B Yamagata, B Victoria.
  
  • Introduction of new subtypes from animal sources.
    
    • Example – influenza antigenic shift.
  • Existing as different stable serotypes that co-circulate in humans.
    
    • Example – rhinovirus (100s of serotypes), poliovirus (3 serotypes), dengue (4 serotypes).
    • Polio – one serotype of polio has been completely eradicated, the vaccine is still a trivalent vaccine though.
      
      • Live-attenuated Sabin vaccine – administration of all 3 at once resulted in virus interference and poor response to one component.
      • Rhinovirus – cause common cold, impossible to make a vaccine against 120 serotypes.
  • Consequence of vaccination.
  • That is why we have to update vaccines on a yearly basis
    
    • H3N1 drift is rapid and many clades co-circulate
    • Some pieces of virus do not change and hence can be targeted by numerous different vaccines
    • Stalk domain: conserved
    • Head domain: variable (make ABS for this)
    • Sympathetic vaccinology - construct headless HA : effort to make a synthetic new vaccine

Question 6

Antigenic variation of Dengue virus

Answer 6

Dengue Virus: Antigenic Variation in Dengue Virus

• Arbovirus - spread by mosquitos
• 1 serotype - flu but 2 - DHF
• Dengue fever is responsible for a lot of hospitalisation each year with 5% fatalities.
• It causes leakage of blood plasma (fluid) from capillaries.
  
  • Cytokine storm
  • This leads to an increased haematocrit and RBC count and a decreased protein count in the blood.
  • Causes severe bruising and bleeding – patients deteriorate even after fever (due to shock).
• Treat with IV fluids.
• Dengue exists as 4 serotypes.
• Antibodies generated against a previous infection can bind but not neutralize, and lead to Antibody Dependent Enhancement (ADE), causing a dengue hemorrhagic fever.
  
  • The dengue viruses use the ab as an access into the monocyte and reproduce inside them.
  • It can stimulate pro-inflammatory molecules like interferons and interleukins - this makes vaccinating against Dengue very dangerous - if you miss a serotype and you set someone up with a vaccine immune response you can make things worse

Question 7

Antibody evasion by HIV

Answer 7

Antibodies against HIV

• HIV env spike gp120 resists neutralisation because:
  
  • Large space between spikes prevent Ab cross-linking.
  • Extensive glycosylation masks Ab epitopes.
  • Functionally important parts of antigen are poorly accessible – CD4 binding site.
• Antibodies that can cross-react with many HIV strains for exist alongside viruses in people that control infection.
• Can make ABS and target the stalk region BUT
  
  • BNabs (Broadly Neutralising Abs) produced as biological therapies can control viral load – this controls viral load but mutants do appear over time of used individually.