Viral genomics

Question 1

What are viruses?

Answer 1

• Very small infectious agents that replicate inside living cells

Question 2

Key properties of viruses

Answer 2

High mutation rates
- This means they give some of the best examples of measurably evolving populations

Evolution occurs at two scales:
- Within host
- Between hosts

Question 3

Viral genome structure

Answer 3

• The genome of a virus may consist of DNA or RNA, which may be single stranded (ss) or double stranded (ds), linear or circular
• Huge diveristy

Example:
- HIV-1 genome: Single stranded RNA, Single genome
- Influenza A: Single stranded RNA, 8 genome segments, each encoding 1 or more genes

Question 4

Classification of viral infections

Answer 4

Acute infections: Sudden, brief onset of infection
- High mutations rate as tend to be RNA
- Limited opportunity for within host evolution as not in the host for long
- Selection for transmission
- Example: Influenza and Sars Cov-2
- Can become chronic in immuno compromised individuals.

Latent persistant infection: Short periods of replication and reactivation of disease, with long periods of latency
- DNA viruses
- Limitied opportunity for within host evolutino due to low mutation rates and long latent periods
- Selection for transmission and dormancy
- Herpes SImplex virus: Latent in the neurons then activated by stress and become active in the Lips and the Eyes

Chronic persistant infection: Viruses that cause acute infections cause persistant infections in immuno dfficient individuals
- On going rapid evolution
- Lots of opportunity for within host evolution.
- Example: HIV, Hep C/ B

Selection acts differently in these different viruses due to their varying life cycle

Question 5

The evolution of viruses

Answer 5

Selection occurs at 2 levels to increase pathogen fitness.

Factors effecting fitness:
o Reproductive rate
o Transmission efficiency
o Ability to evade immune response
o Capacity to adapt

1) Within host evolution

• individual scale
• Selection pressure to maximize within-host fitness selecting for:
  o Evasion of the immune system (Antigenic evolution)
  o Resistance to anti-viral/ bacterial treatments
  o Maximisation of replication (pathogen load also linked to transmissibilty) -> selection on both scales
• get multiple sequences from same individual at different time.
• Examples: Evolution of HIV envelope during infection to evade antibodies (Non- synonymous> synonymous)
• -> Much faster rate of evolution within host than between host seen by constructing phylogenetic tree of sequences from one individual compared to consensus sequence from many)
• -> Evidence that mutations are involved in host immune evasion -> different mutations in different strains depending on the host immune system (Data from 34 serially sampled HIV individuals)
• Within host evolution leads to toggling as viruses move between individuals.

2) Population scale evolution

• Level of the population.
• Selection pressure to maximise between host fitness effecting:
  o Host behaviour
  o Symptoms
  o Pathogen infectiousness (correlated with pathogen load)
  o Virion stability
  o Length of infectiousness
  o Population immunity
• Get consensus sequence from different individuals at different times.
• Example: Toxoplasma alters the behaviour of a rodent host (reduced aversion to cats) to increase the probability of predation by cats and therefore increased contact.
• Example: ladder like selection between years due to selection for different variants. virus evolves in the tropics and seeds variants into the hemispheres.

Question 6

Using phylogenetic data to understand viral origins

Answer 6

Phylogenics can be used to track the source and place of the outbreak

Example:
- Phylogenoegraphic and moleculare clocks place the ancestar group of HIV in Kinshasa (Congo)

• Hypothesis: HIV 1 due of vaccination of 60 million people in Congo that had been cultured with Chimpanzee kidneys -> allowed the transfer
• But phylogenetic analyses shows that group M originated before the vaccination campaign supporting model of natural tranfer
• Analyses shows HIV clades nested within SIV, suggesting multiple cross species shifts.(Likely chimps for HIV-M -> look at chimp disitribution)
• It then spread outwards across central Africa along calonial railway and ferryboat transport systems.

Example: Swine flu emerged in humans after evolving in pigs in Mexico

Question 7

Uses of viral phylogenetics

Answer 7

Cluster busting: Generate networks of similair consensus sequences from different individuals. Clustering suggests rapidly growing epidemic.

Example: HIV-1 public health analyses

Forensics: Investigate and solve legal and criminal issues

Example: The Florda dentist (1980s)
- HIV-1 positive dentist was thought to pass the virus to his patients
- Evidence: patients had HIV sequences closer to dentist than other controls
- This was done by constructing a phylogentic tree of strains for different individuals and comparing how close the were.
- However, cannot infer transmission events due to varying degrees of within host evolution.

Problem: Genomes of strains sampled from individuals who are known to have infected eachother do not resemble each other due to within host evolution

Example: Sweden rape case
- Phylogenetic analyses proved that HIV-1 strains between two individuals were more closely related to each other than the controls
- Male and female also shared two distinct genetic variants of HIV-1 suggesting tranmission of more than 1 infectious unit.

Question 8

Other factors affecting the levels of selection

Answer 8

The type of virus -> is it acute, chronic, latent?

Has it just emerged or has it been around for a while?
- In newely emergent pathogems, mutations that are beneficial within and between host arise quickely (e.g. mutations that increase replication rate) e.g. D614 gene mutation in SARs COV-2
- In well adapted viruses, mutation emerge that benefit the specific host (less well adapted when enter the new host)

Question 9

Short vs long sited evolution trade off

Answer 9

Within host evolution (escape from immune system) may inhibit between host evolution (increased transmissibilty
- They may inhibit the infectious process
- They mean that the virus is specifically adapted to host, so when transmitted it is less effective against the next host. (evolved to specific MHC)

Within host evolutoin can result in reduced fitness as virulence is maximised. R0 is greatest at intermediate virulence where there is a balance between infection (tranmission) time and transmission rate. Increasing virulence away from an intermediate level will lead to reduction in R0 as no longer balancing tranmission time and rate.

Example: HIV
- After long period, CD4 cells are depleted so HIV switches its receptor to infect Macrophages
- This makes HIV less efficient at infecting CD4 cells when it is transmitted to a new host.

• Heavy glycosylation of HIV evolves during infection as increases resistance to antibodies, however, glycosylation means it is more easily trapped and inhibited by agents in the transmission fluids/ more likely to be targeted by the innate immune system.

Solution
o Germline lineages (i.e. transmission of lineages that haven’t evolved within host)
o Life history strategies leading to low within-host evolution
-> Decreased mutation rate and increased viral generation time

Question 10

Interesting example: SARS Cov-2

Answer 10

Infection travels between individuals as acute infections (little individual level selection)

Occasionally there is a chronic infection where within host evolution can lead to a new variant by chance

Within host evolution leading to advatages at a between host scale.