MHC & HIV

Question 1

What is MHC?

Answer 1

A key element of the cellular arm of the adaptive immune system - protects against intracellular pathogens
MHC proteins expressed on surface of many cell types - interact with pathogen peptides

Question 2

Where is the human MHC gene located?

Answer 2

On chromosome 6

Question 3

What are human MHC genes often called?

Answer 3

HLA - human leukocyte antigen
Refers to the fact these are transplant antigens - expressed on all cell surfaces and are highly polymorphic
Means can lead to rejection in transplanted organs

Question 4

How do MHC proteins work with T cells?

Answer 4

Work with T cell receptors to recognise peptide fragments from pathogens
Sequence-dependent recognition
If matched triggers protective cytotoxic T-cell (CTL response) - cell harbouring pathogen is killed

Question 5

How do MHC Class I proteins function?

Answer 5

3 domains which have different functions

Have an antigen-binding site (ABS): pathogen peptides bound, presented to T cell receptor, triggers cytotoxic response

Question 6

How does the host CTL immune response work?

Answer 6

MHC Class I molecules bind 9 amino acids
Requires molecular ‘match’ between ABS and epitope
Changes of amino acids in either can prevent binding

Question 7

How can you estimate rate of evolution?

Answer 7

Compare Ks to Ka in same gene:

• if Ks > Ka usual situation, purifying selection
• if Ka > Ks amino acid replacement faster than synonymous evolution, signifies adaptive/’positive’ darwinian selection

Question 8

How do the Ks/Ka ratios compare for different domains in MHC Class I proteins?

Answer 8

The ABS has a Ka much higher than Ks - indicates strong adaptive evolution, ABS must recognise peptides from a wide range of pathogens so divergence selected
The extracellular and transmembrane domains both have Ks greater than Ka, suggests purifying selection - transmembrane domain highly conserved

Question 9

How does the allele frequency distribution look in MHC?

Answer 9

MHC genes have:
Very high diversity of functionally distinct alleles
Flat allele distribution - suggests balancing selection keeping alleles in population, frequency-dependent/heterozygous advantage

Question 10

What is trans-specific evolution?

Answer 10

When the closest relative of an allele is found within the present day genome of another species

Question 11

How do humans and chimps show trans-specific polymorphisms?

Answer 11

Average time since 2 neutral alleles shared an ancestor = 2Ne gens = 400,000 years
Human-chimp split = ~10 million years
Shows diversity has been maintained as alleles have not gone extinct

Question 12

What is the evidence for adaptive evolution in the MHC?

Answer 12

Overdispersed (flat) allele frequency distribution
Positive selection in antigen binding site (dN/dS)
Transpecific polymorphisms - maintained in population for longer time than between speciation events

Question 13

What are the effects of HIV on population genetics of the host?

Answer 13

Significantly reduced life expectancy

Children die very young

Question 14

How are MHC alleles associated with rate of progression to AIDS?

Answer 14

Increase rate of progression: B35, B53, A1-B8
Decrease rate of progression: B57 effect associated with low fitness of CTL escape variants selected by this allele, B27

Question 15

How do HLA alleles protect humans?

Answer 15

Some HLA alleles protect against HIV disease - delay onset of AIDS
Do not protect against infection
Heterozygosity at HLA genes is protective - greater chance of protective allele

Question 16

What are HIV-resistance genes?

Answer 16

HIV receptor CCR5 partial deletion in delta 32:

• recessive resistance to HIV infection
• absent in African populations, found in Scotland

CCR5-binding protein - CCL31:

• multiple copies
• copy number varies in all populations

Question 17

Is HIV selecting for resistance?

Answer 17

Genetic variation in CCL3L1 genes
Some variants confer resistance
Individuals of susceptible types are: more likely to be infected, die more quickly when infected
But controversial result

Question 18

How do RNA viruses evolve?

Answer 18

Rapid replication & high mutation rates = fast evolution
Generation time ~1-2 days
Mutation rate 10,000-fold higher than nuclear DNA
Rate of synonymous evolution ~1% per year

Question 19

What is an example of drug resistance in HIV?

Answer 19

Antiretroviral drug lamivudine inhibits HIV reverse transcriptase
High level resistance due to 1 mutation - methionine to valine at amino acid 184 in active site

Question 20

How can we tell drug resistance carries a cost?

Answer 20

Mutants decrease when drug is stopped - indicates WT selected for in absence of drug

Question 21

What selection is conferred by the host?

Answer 21

Host CTL recognise specific ‘epitopes’ (short peptide sequences)

1. Epitopes depend on alleles at MHC
2. Mutations in CTL epitopes lead to loss of recognition

Question 22

What is an example of fast evolution of immune escape?

Answer 22

SIV - animal model of HIV
Experimental infection with MHC-matched strain of SIV
Virus sequenced from 2 weeks post infection
Only variation was in epitope recognised by the MHC
“CTL escape”

Question 23

How do the MHC and the pathogen contribute to eachother’s evolution?

Answer 23

Mutations in CTL epitope increase in frequency
Mutations in CTL epitope appeared after CTL responses arose
MHC selects for diversity of pathogens
Pathogen selects for diversity in MHC
‘Arms race’

Question 24

How do fitness effects of CTL mutations depend on host genotype?

Answer 24

‘Escape’ mutations increase fitness where CTL response present
In absence of specific CTL response, may reduce fitness - like drug resistance mutations
Evidence from HIV transmitted from mother to infant

Question 25

how does CTL escape occur in maternally transmitted HIV1?

Answer 25

Mother & child share 1 MHC Class I allele
If HIV has evolved an escape mutation in mother & virus is transmitted
Child may inherit:
- the selecting MHC allele, and escape mutant persists
- the non-selecting allele, and escape mutant lost (has a lower fitness in absence of selecting allele)

Question 26

What are the selective processes in HIV?

Answer 26

1. Rapid selection for resistance to drugs
   - strong selective pressure, high mutation rate, reversion in absence of drug
2. Selection for escape from CTL response
   - Ka/Ks shows evidence of selection in env
   - Evolution only within epitopes, strong CTL response
   - Reversion in absence of selecting allele