Download An example HIV

An example
How does an evolutionary perspective integrate
information generated in other biological disciplines?
HIV
Human Immunodeficiency virus
• Set the stage
• You come up with a
list of evolutionary
q
questions
• How evolutionary
has an evolutionary
perspective informed
our understanding
The problem
• Recognized 1981
• Infected 65 million
people
• 25 million
illi h
have di
died
d
• Virtually 100% fatal
• 2020 AIDs will kill 90
million
• 5% of all deaths
worldwide
• 70 % in SubSaharan Africa
• Thought
Th
ht to
t be
b mostt
infectious disease to
affect humankind
ttp://data.unaids.org/pub/GlobalReport/2006/2006_GRExecutiveSummary_en.pdf
AIDs epidemic
• Infection rates 15-45yr
15 45yr
• 2/3 in sub-Sarahan
Africa
• % adults
d l iinfected
f
d
•
•
•
•
37.3 Botswana
24.6 Zimbabwe
38 8 Swaziland
38.8
28.9 Lesothos
• Reduced life
expectancy from 62
to 47 years
• 90 % in poor
countries
t i off
Southern
p
hemisphere
UNAIDS 2002
• Rapid increase
What is HIV?
• Intracellular
p
parasite
• Enters host
through body
fluids
• Parasitizes cells
of human
i
immune
system
t
– macrophages
and T cells
• Simple structure
• Co-opts cell’s
machinery for
replication
Freeman and Heron 2004
How does your body react?
Acute state
• Explosive replication of virus
• T-cells plummet as they are destroyed by viral replication
Chronic state
• HIV replication slows – fewer host cells/Immune response
• Immune system activated – CD4 T fight HIV/other pathogens
AIDS
• Naïve T-cells are
depleted
• Slower production
with age
• Opportunistic
infections by
bacteria and fungus
that do not normally
cause disease
proliferate
Nelson et al. 2002
How can we fight HIV?
Before infection
Ghys et al. 2002
Men in Amsterdam
D k
Dukers
ett al.l 2002
•
•
•
•
Reduce riskyy behavior
Safe sex
Used needle exchange
Effective?
How can we fight HIV?
After infection
• Treat with drugs
• Drug
D
ttargets?
t ?
• Interfere with cell’s surface proteins
to prevent attachment
• Prevent reverse transcription
• Block integrase protein
• Prevent HIV protease enzyme from
cleaving viral precursors into mature
components for virions
Freeman and Heron 2004
How can we fight HIV?
After infection
• Treat with drugs
• AZT mimics
i i normall th
thymidine
idi b
butt llacks
k h
hydroxyl
d
l group
(azide group instead)
• Halts replication
What is going on here?!?
• Sometimes in host DNA
• Short-lived effectiveness
AZT
Thymidine
Freeman and Heron 2004
List of evolutionary questions
• Where did this disease come from anyway?
• Whyy do diseases shift hosts?
• How often do diseases shift hosts?
• Why do diseases kill their hosts?
• Is there any natural resistance to HIV in the human
population?
• Why are there more resistant humans in some parts of the
world
ld vs. others?
th ?
• Why do drugs stop working?
• Where does variation in the virus come from?
• How does HIV resistance evolve?
• Why does human behavior change?
• How much does perceived risk influence behavior?
• Are people relying upon conscientious behavior of others?
Where did this disease come from
anyway?
• Genome and life cycle similar to SIV
(Simian immunodeficiency viruses) but
doesn’t cause disease in primates
p
Is there a history of the host shift
recorded in the genes?
• Sequenced reverse transcriptase
• Phylogeny reconstruction
• Two main types of HIV represent
separate host shifts
• HIV-1 causes most human disease
How did host shift occur?
• Chimps hunted to food in Africa
How many times has this
happened?
Hahn et al. 2000
How many transmission
events?
• Phylogeny based on virion
surface proteins
p
• Three transmission events
• HIV-1 group M most diverse
and causes majority of AIDs
infectons
When did transmission
happen?
• Samples
p
collected over the last
two decades
• Rapid divergence has occurred
over that short time
• Plotted divergence relative to
time of collection
Hahn et al. 2000
When did the host shift
happen?
159 samples of M HIV1
• Scatter plot of genetic difference
between original
g
collection
(common ancestors) and virions
collected each subsequent year
• Greater divergence with time
• Slope of the line indicates rate of
divergence
• Back
B k extrapolated
t
l t d rate
t to
t time
ti
when there was no genetic
variation
• Host shift occurred between 19151941 with 95% confidence (1931
is best fit)
Korber et al 2000
List of evolutionary questions
• Where did this disease come from anyway?
• Is there anyy natural resistance to HIV in the human
population?
How could you study this?
• Examine people have been repeatedly been exposed but not
infected
• Resistant people have unusual coreceptor molecules that
thwart entry of HIV into cells (Samon et al. 1998)
• CCR5
CCR5-Δ32
Δ32 has 32 base pair deletion in sequence
Do human populations differ in frequency of CCR5-Δ
32?
Distribution of CCR5-∆32
~ max 17 %
Whyy higher
g
in N. Europe?
p
Test?
• Drift
• Also confers resistance to
bubonic plague – killed 30
3040% of Europeans in 1340’s
• Or small pox – killed more
people
l b
but over a llonger time
i
period
Limborskaa et al. 2002
Drift, plague or small pox?
• Origin of CCR5-Δ32 estimated to be 1,100 years ago
• Plague
• Two
T
greatt plague
l
outbreaks
tb k
• Black death 1346-1352 (killed 40%) and Great Plague 1665-1666
(killed 20%)
• Intermittent outbreaks for ~400 yrs (killed 10%)
• Disappeared 1750
• Affected all ages equally
• Small pox
• Epidemics occurred in Europe 2,000 years ago
• Constant low level of p
presence ((killed 30%))
• Eradicated 1978
• Affects children disproportionately
Galvani, A.P. and Slatkin M 2003. Evaluating plague and small pox as historical selective pressures for the
CCR5-delta32 HIV resistance allele. PNAS 100:15276-15279
Evolutionary model evaluates three
hypotheses
Subscripts
x = age class
t = time
CCR5, CCR5
Susceptible homozyotes
CCR5, CCR5-Δ32
Background
Fedundity - # female offspring
mortality
Genotypic
born to female age x
resistance
Mortality
from
disease
Number of females in the
age class x at time t
Heterozygotes
CCR5-Δ32, CCR5-Δ32
Resistant homozygotes
yg
Galvani and Slatkin 2003
Drift, plague or small pox?
• M
Model
d l results
lt
• Plague could not generate sufficient selection pressure to explain
current frequency in such a short time
• Small box alone can account for pattern
• Genetic drift also unlikely to lead to high frequency
0.8 % Plague
10 % Small pox
Galvani and Slatkin 2003
Drift, plague or small pox?
• M
Model
d l results
lt
• Plague could not generate sufficient selection pressure to explain
current frequency in such a short time
• Small box alone can account for pattern
• Genetic drift also unlikely to lead to high frequency
• Geographical distribution of the allele
• Bubonic plague more intense in central Europe, small pox in
Scandinavian populations
• Spread via Viking dispersal
• Clinical effect of the deletion
• CCR5-∆32 probably has other adverse fitness effects
• Should have been reduced in population
Galvani, A.P. and Slatkin M 2003. Evaluating plague and small pox as historical selective pressures for the
CCR5-delta32 HIV resistance allele. PNAS 100:15276-15279
List of evolutionary questions
• Where did this disease come from anyway?
• Is there anyy natural resistance to HIV in the human
population?
• Why are there more resistant humans in some parts of the
world vs
vs. others?
• Why do drugs stop working?
• Host physiology?
• Viral
Vi l evolution?
l ti ?
Viral evolution?
• Cells cultured from two patients receiving AZT over time
• Does the amount of AZT required to kill the virus change over
time?
Larder et al. 1989
Highest mutation rate
ever characterized
• Reverse transcriptase makes
~0.2 errors p
per g
genome p
per
replication cycle
• RNA polymerase also prone to
errors
• Extremely high rates of
replication
• Generation
G
ti time
ti
off 2.5
25d
days
• Produces 1010 – 1012 new
virions each dayy
• Frequent recombination
produces new strains
• Frequency-dependent
selection favors variation
Freeman and Heron 2004
Hypervariable
yp
env gene
What changes could lead to
resistance to AZT?
• Change in binding site
• Some contain amino acid
substitutions
b i i
that
h llessen affinity
ffi i to
AZT
• More successful in replication
p
• Increase in frequency in host
Cohen 1993
Evolution of resistance
How could you
test whether
this is really
happening?
Rambaut et al. 2004
With-host
evolution
• 9 patients taking
AZT
• Viral DNA
sampled
overtime
• What should the
phylogeny look
lik ?
like?
• Continual drug
and immune
driven selection
• Selective
replacement of
strains overtime
Palella et al. 2000
What is the next
strategy?
t t
?
• Cocktails (HAART)
• Interfere with cell’s
surface proteins to
prevent attachment
• Prevent formation of
DNA
• Block integrase protien
• Prevent HIV protease
enzyme from cleaving
viral precursors into
mature components for
virions
ii
Multiple drug resistance
Rambaut et al. 2004
ttp://data.unaids.org/pub/GlobalReport/2006/2006_GR-ExecutiveSummary_en.pdf
HIV and AIDS
E l ti
Evolutionary
process att ttwo levels
l
l
• Genetic differences among
g individuals
• Human resistance - CCR5-∆32 coreceptor
• Virus mutants - Sequence coding active site among
individuals
• Sorting among variants
• Historical diseases caused selection in humans
• Selection
S
off viruses within infected
f
person by drugs
• Changes in the proportions of individuals in populations
• Geographic
g p
variation in human resistance
• Host shift in virus
“Felix qui potuit rerum cognoscere causas”
Happy is the person who has been able to
learn the causes of things
Virgil