HIV / AIDS stats
Evolution in Action 1
• at least 60 million infected people since 1981
• 20 million already dead
• 90 million deaths projected for 2020
• causes !5% of deaths worldwide (5th
leading cause of death)
•
still behind cancer, heart attack, stroke, and respiratory
infections, all of which predominantly kill the elderly.
Retroviruses
The New Black Death
•
•
HIV is a two-stranded RNA-based virus.
•
It depends upon ‘reverse transcription’ within the
host cell to convert itself into DNA.
•
Each virion carries with it:
Its genetic code needs to be translated into DNA
before it can transcribe anything.
•
•
•
reverse transcriptase
integrase
protease
HIV virion
(capsule + RNA + enzymes)
HIV virion binds
to cell receptors
(CD4 & coreceptor)
reverse transcriptase
makes DNA from virion’s
RNA
integrase splices HIV DNA
into host cell chromosome;
HIV mRNA is transcribed.
new HIV proteins are made
by host cell & assembled
into virions
images: http://www.chemistry.wustl.edu/~edudev/LabTutorials/HIV/DrugStrategies.html
Progression of HIV infection
AZT
•
because they have unique biology, retroviruses would
•
a promising therapy based on tricking reverse
•
instead of normal thymidine, RT inserts AZide
•
seem to be easy targets for medical intervention.
transcriptase into inserting a terminating base.
Thymidine.
in early trials AZT worked: it stopped the decline in
macrophages and T cells.
but AZT stops working, quickly
How AZT works
Resistance (% Viability)
o)
m
e(
tim
o)
m
e(
tim
AZT Concentration (µM)
azide group
Why does resistance
develop?
• the patient’s own cells may change to
discriminate against AZT
•
•
excluding it from the cell or failing to phosphorylate it.
e.g., less thymidine kinase
• the virus could evolve to avoid using AZT
during reverse transcription.
Alterations in the RT active site evolve very
quickly
µ
*
*
susceptible
partly resistant
highly resistant
Bad copy makes good
evolvability
•
many thousands of generations of HIV
within victim.
•
Divergence at the gp120binding site gene:
chronic phase.
T-cell counts collapse
8% divergence
generation time est’d at 1.2 days (Perelson et al. 2002)
• reverse transcriptase is highly error prone.
•
•
no error correction mechanism.
human vs. chimp
among highest mutation rates yet measured
•
50% of transcripts are mutated
= abundant opportunity for natural selection
from Shankarappa et al. 1999
Compensatory Evolution
8%
10y ! 3,000 generations
• AZT-selective reverse transcriptase will copy
more slowly than non-selective RT.
4 x divergence between human & chimp (2%)
human & chimp diverged 5.4 mya
•
this fitness trade-off suggests that removal of therapy should
lead to a reversion to non-selective forms.
• But selection for efficiency is relentless:
! 500,000 generations
x2
= 1,000,000 generations
•
compensatory evolution makes resistant forms more
efficient with longer exposure to the drug.
1,300x faster sequence evolution
Multidrug Therapies
Q: Why Kill Your Host?
• rt, protease, fusion, integrase inhibitor cocktails
work by multiplying the odds
• chance of resistance to drug A = 1/1 000 000
• chance of resistance to drug B = 1/1 000 000
• chance of resistance to A & B = (1/1 000 000)
multi-drug therapies have been successful... for a
while:
2
•
•
•
do not cure HIV infection
cannot be tolerated indefinitely
protease inhibitor
images: http://www.chemistry.wustl.edu/~edudev/LabTutorials/HIV/DrugStrategies.html
• Death of the host means death of all virions
carried by the host.
• No chance of further transmission.
A1: Evolution does not think ahead.
A2: Virulence usually correlated with
harm to host.
Levels of Selection
• Fitness of a virion
= intrahost success1 x interhost2 transmission.
1: selection within infected host favours the viral
particles that multiply most rapidly.
•these successful intrahost types may degrade host
performance, potential for transmission.
2. selection on transmission between hosts may
favour lower virulence.
• a virus that kills its host too fast is committing suicide.
Offspring
Parent
Modes of Transmission
-
!
!
-
+
+
-- -
HIV Suicide?
• HIV within-host selection favours novel
epitopes (motifs of surface proteins).
• virions switch from CCR5 to CXCR4
coreceptors over time within hosts.
• host X4 T-cells increase cell division with
protracted infection.
• strongly decreases transmissability.
• uninfected hosts have very low CXCR4
cell division rates
HIV is going both ways
• current course of infection by HIV-1 creates
high viral titres before degradation of health
• horizontal transmission & high virulence
being selected for, but...
• more benign strains (e.g., HIV-2) spreading
slowly but steadily.
• e.g., Sydney Bloodbank Cohort?
William Hamilton
Distribution of resistant CCR5 mutants
Genetic Variation for Resistance
• some people are more resistant to HIV than
others.
• the Scandinavian mechanism involves a
deletion in the CCR5 receptor (CCR5-"32).
• is this pattern due to selection?
• if so, can a recent origin of HIV explain it?