Evolution & Medicine - Lecture 36 Summary

HIV/AIDS

• HIV is a lentivirus that causes AIDS.
• Infection occurs through bodily fluids.
• Affects 0.6% of the population, about 3.5% of deaths worldwide.
• The virus infects and causes the failure of the immune system.
• New therapies with anti-retroviral drugs will delay, or even stop progression to AIDS, but will not cure.

Sequencing Virus

• Using PCR, viral genomes or pieces can be isolated from infected patients.
• Phylogenetic trees trace the relationships between species, DNA, or protein sequences.
• Trees can be reconstructed computationally from an alignment of DNA sequence.

Tree of HIV Sequences

• Multiple sequences come from each patient.
• Sequences are more closely related within a patient than between.

Infections from Multiple Viruses

• Each patient may have more than one viral sequence because they were infected with multiple viruses.

The Viruses are Changing

• The multiple sequences may be due to the viruses changing within a patient.
• Viruses within a patient are more similar than between.
• The pattern of the tree suggests a single point entry of a virus and then diversification.

The HIV Sequence Changes

• Proximate: the mechanism by which the change is occurring.
• Ultimate: what is causing the change.

Mechanism of Change

• HIV is a lentivirus – a sort of retrovirus.
• It has an RNA genome.
• Infects and damages immune system cells.

Reverse Transcription

• Reverse transcriptase is an enzyme that turns RNA sequence back into DNA.
• Reverse Transcription is more error-prone than DNA replication, so lots of variants are formed.

Is it Just a Mutation?

• All the variants found encode active, working viruses.

All You Require for Natural Selection Is:

• Variation - Individuals in a population vary from one another.
• Inheritance - Parents pass on their traits to their offspring genetically.
• Selection - Some variants reproduce more than others.
• Time - Successful variations accumulate over many generations.

Selection?

• HIV variants are selected for or against.
  • The immune system
  • Drug regimen
  • Changes in the receptor
  • Tropism in tissues

So, HIV Evolves?

• AIDS viruses from patients on anti-retrovirals have a different pattern of variation from those that are not.
• Most clear is the advent of resistant viruses – first to AZT, now to triple therapy or HAART (high active retroviral therapy).

Consequences

• The HIV genome holds the record for the fastest evolving thing we know of.
• Patients don’t have a virus; they have a vast armada of viral variants.
• Resistance to therapy, even complex therapy, arises rapidly.
• Making effective vaccines is incredibly hard.

The HIV Armada

• Estimates of 10^8 - 5 x 10^{10} provirus-containing cells in a patient.
• Each one may be genetically distinct, so assuming 1 provirus / cell we have up to 5 x 10^{10} different variants

HIV vs Covid 19

• Covid 19 reported to evolve at 8.4 x 10-4 sub/base/year

Is This an Isolated Case?

• Many pathogens evolve within the host in the same way.
• Antibiotic resistance spreading through a population of bacteria is also an evolutionary process.
• Even our own genome evolves in response to pathogens (e.g., CFTR variants as possible resistance to plague).

Evolution & Medicine

• Evolutionary thinking can help us understand and better respond to pathogens like HIV.
• Evolution is a key-way that pathogens respond to hosts and therapy.