viral infections

Question 1

significance of viral (obligate IC parasite) proteins being easy targets

Answer 1

processed and presented by MHC class I, with internal viral proteins being possible targets of cellular immunity as they vary less than surface antigens

Question 2

effect of cellular immunity on viral infection

Answer 2

cellular immunity clears viral infection but is short lived, so viruses that persist must evade cellular immunity (e.g. herpes viruses)

Question 3

give pathway of MHC class I antigen presentation

Answer 3

viral peptide synthesised inside infected cell -> chopped by proteosome -> into ER -> picked up by MHC class I molecules -> transport up to Golgi and membrane -> present peptides to CTLs

Question 4

example of viral regulation of MHC class I antigen presentation

Answer 4

encode proteins which stop transporter being able to put foreign peptides into ER for MHC class I presentation

Question 5

mechanisms to prevent viral regulation of MHC class I antigen presentation

Answer 5

evasion of antigen loading to tapasin from cytoplasm to ER lumen, modulation of TAP function and prevention of MHC transport, interfering with MHC presentation at cell surface

Question 6

evasion of antigen loading to TAP: CBV, HSV and CMV

Answer 6

CBV: cannot be processed by proteasome, HSV: processed peptide has blocked access to TAP, CMV: ATP stops binding to TAP (preventing translocation)

Question 7

modulation of tapasin function and prevention of MHC transport: CMV and adenovirus

Answer 7

CMV: binds tapasin to prevent peptides being loaded to MHC, adenovirus: prevention of recruitment of TAP to tapasin (and retention of MHC in endoplasmic reticulum)

Question 8

interfering with MHC presentation at cell surface: KSHV

Answer 8

KSHV: induces polyubiquitinylation and internalisation of MHC (from internalised endosome, MHC passed to lysosomes where it is degraded)

Question 9

describe how viruses avoid natural killing

Answer 9

miss self mechanism: normal healthy cells display MHC at their surface, and any cells that don’t display MHC are detected by NK cells and killed, so viruses encode MHC analogues or upregulate MHC to avoid NK destruction

Question 10

describe antigenic variation and sources

Answer 10

continued rapid evolution driven by antigenic pressure from host (e.g. influenza antigenic drift, HIV quasispecies), or introduction of new subtypes from animal source (e.g. influenza antigenic shift), or viruses which exist as different genetically stable sterotypes (e.g. rhinovirus)

Question 11

what is the major antigen of a virus, and properties

Answer 11

haemagglutinin, which has a very variable head domain (evolves all time), and a less variable stalk domain

Question 12

consequence on vaccines of antigenic drift

Answer 12

vaccines updated every year to best represent circulating strains due to evolution of variable head, mapped by anitgen cartography (can get it wrong if selected strain is poor match with predominating circulating virus)

Question 13

due to head variability, what do most broadly neutralising (bn) antibodies target

Answer 13

haemagglutinin stalk, as these are constant (basis for a “universal virus antibody)

Question 14

3 ways to skewer antibody response towards haemagglutinin2 stalk region

Answer 14

headless haemagglutinin, hyperglycosylating haemagglutinin1 head domain, peptides against fusion peptide and ectodomain, make haemagglutinin stem more spread out (e.g. ferritin based nanoparticles), sequential immunisation with chimeric haemagglutinin

Question 15

describe 4 ways by which HIV resists neutralisation by antibodies

Answer 15

large spaces between haemagglutinin spikes to prevent antibody crosslinking, extensive glycosylation to mask antibody epitopes, poorly accessible functionally important parts of molecule, huge variation in redundant amino acids against highly specific antibodies

Question 16

describe broadly neutralising antibodies to HIV in some infected people

Answer 16

control viral load as antibodies can cross react with many HIV strains by binding to stalk region

Question 17

negative aspect of broadly neutralising antibodies which control viral load

Answer 17

viruses evolve and produce escape mutants

Question 18

what virus causes common cold, and consequence of vaccine production

Answer 18

human rhinovirus (exists as hundreds of antigenically distinct serotypes that co-circulate, so impossible to make vaccine against them all)

Question 19

number of serotypes of poliovirus, and consequence of vaccine (Sabin, not Salk) production

Answer 19

3, so with Sabin vaccine must have administration of all 3 at once (one serotype may be outcompeted for replication, so poor response requiring larger dose for this serotype in vaccine)

Question 20

Dengue (arbovirus) feature and detection

Answer 20

4 serotypes, and if infected twice, becomes Dengue haemorrhagic fever, with a cytokine storm with leakage of blood plasma from capillaries (detected by increased RBC and decreased blood protein)

Question 21

Dengue haemmorhagic fever signs and treatment

Answer 21

tendency to severe bruising and bleeding, with deterioration even after fever drops (shock so treat with i.v. fluid replacement)

Question 22

describe how Dengue virus can cause Dengue haemorrhagic fever

Answer 22

so antibody generated against previous infection can bind but not neutralise, forming immune complexes of virus and antibody, which are picked up by Fc receptor on macrophages, leading to antibody dependent enhancement (can infect other cells including macrophages), causing Dengue haemorrhagic fever (new infected immune cells produce cytokine storm with many pro-inflammatory molecules)

Question 23

consequence of vaccination on Dengue virus

Answer 23

must target all 4 serotypes and neutralise, preventing Dengue haemorrhagic fever

Question 24

describe virus-mediated immunosuppression

Answer 24

some viruses (e.g. measles) infect memory lymphocytes, so cause a decrease in immunological memory, so are more susceptible to other infections also