3: Viral evasion of Host immunity Flashcards
Explain how viruses escape host innate and cellular immune mechanisms and recall examples
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Describe cellular immunity in relation to viruses
Viruses are intracellular pathogens so viral proteins are easy targets for presentation by MHC
Cellular immunity - clears infection but is SHORT-LIVED
Internal viral proteins are MAIN targets (vary less than surface proteins)
Viruses must evade cellular immunity in order to persist
How is MHC class 1 antigen presentation regulated?
Viral peptide cleaved into 4 pieces within the cytosol by proteasome
Peptide molecules enter endoplasmic reticulum Loaded onto MHC class 1 Transported via golgi to surface membrane
Binding of T-cell receptor + CD8 -> release of toxic proteins that enter and kill the infected cell
Virus replication stopped since it cannot replicate without host cell
Examples of evasion of antigen detection via MHC presentation
EBV: only makes EBNA1 2which CANNOT be processed by proteasome
Herpes simplex: ICP47 blocks access of processed peptide to TAP transporter on ER
CMV:
- US6 stopping ATP binding to TAP, preventing translocation
- US3 binds to tapasin, prevents loading of peptide onto MHC within the ER
Adenovirus: prevents recruitment of TAP to tapasin (thus preventing loading) and also retains MHC in the ER (stops it from moving out)
KSHV: kk3 protein induces internalisation and lysis of MHC molecule
HPV: E5 protein holds MHC in ER
How are NK cells involved in viral infection
NK cells are part of INNATE immunity
They detect and kill cells that are NOT expressing any MHC
Viruses that stop MHC presentation are killed by NK cells
(Adenovirus, KSHV, HPV)
HCMV: encode MHC analogues (fake) to present on cell surface
How do viruses avoid humoral immunity?
Humoral = antibodies/B-cells
ANTIGENIC VARIABILITY
1. Continued rapid evolution of viruses due to antigenic pressure from host (e.g. Influenza antigenic drift, HIV)
2. New subtypes from animals (influenza)
3. Existing as different SEROTYPES which are genetically stable that co-circulate in humans
(rhinovirus has 100 serotypes, poliovirus 3 serotypes, Dengue 4)
Target antigen in influenza?
Haemaglutinin
Head and stalk domains
Has variable and conserved AA sequences
- Head domain is MOST variable
- Stalk domain quite conserved, probably because it is necessary for function or there is no pressure for it to change since 99% of our antibodies bind to the head
Example of influenza
Influenza A virus H3N2
Evolved over many years by antigenic DRIFT
Drift is rapid, many clades co-circulate
28 vaccine updates in last 50 years, 6 in last 10 years
How do new vaccine antibodies work against influenza?
Broadly neutralising Abs (bnAbs)
Target the STALK not the head
Could lead to a UNIVERSAL influenza vaccine
Ways to stimulate bnAb production?
- Immunisation with headless HA
2. Hyperglycosylated HA1 head domain (cover with sugar)
Explain antibody evasion by HIV
The HIV spike protein gp120 is HIGHLY variable
- glycosylation masks antibody epitopes (glycan shield)
- Large space between spikes prevents Ab cross-linking
bnAbs for HIV do exist, but none are potent enough yet, and some have escape mutations
Explain antibody evasion by rhinovirus
Exists as more than 120 serotypes than can co-circulate
Impossible to make vaccine for all of them
How many serotypes does polio have?
3
This requires a trivalent polio virus vaccine
How many serotypes does Dengue virus have?
4
Dengue causes haemorrhagic fever (leakage of blood plasma from capillaries)
Explain antibody dependent enhancement of Dengue
Antibody generated against 1 serotype from previous infection can bind to another serotype on subsequent infection but CANT NEUTRALISE
This Ab/virus complex can be detected by monocytes
Virus can now infect monocytes
Virus can replicate more
ALSO causes cytokine storm causing leaky endothelium -> haemorrhagic fever
