Download HIV/AIDS as a Microcosm for the Study of Evolution

HIV/AIDS as a Microcosm for
the Study of Evolution
Questions
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What is HIV?
How does it “work”?
How does the immune system respond?
What is the course of a typical infection?
Why do drugs have limited effectiveness?
Why does the immune system not defeat
infection?
• Why are some people resistant to HIV?
• Where did HIV come from?
• Why have HIV vaccines been unsuccessful?
What does this have to do with
evolution?
• How populations change through time in
response to changes in their environments
— mutation, variation, natural selection,
adaptation
• How new species come into being —
biological diversity, phylogeny
HIV - History and impact
• First recognized 1981
• 60 million infected so far
• 1/3 have already died (5% of all deaths
world-wide = 8,000/day)
• Estimated 90 million deaths by 2020
Prevalence of HIV-1 in adults age 15-45 (2001)
What is HIV?
• RNA retrovirus
• Virion contains
– 2 identical RNA molecules
– 3 proteins (including reverse transcriptase)
• Specific to two components of human immune
system — T cells and macrophages
• Enters cells by attaching first to membrane protein
CD4 and then to a second coreceptor protein
(typically CCR5)
HIV life cycle in host cell
The course of a typical HIV infection within
an individual
AZT: an anti-HIV drug
• AZT = azidothymidine, a thymine mimic
• “Fools” reverse transcriptase into inserting AZT in
place of T when making DNA copies of viral RNA
• Stops reverse transcription, prevents viral
replication (= reproduction)
• Causes serious side effects because DNA
polymerase may also be “fooled” during
replication of host cell genome
Effectiveness of AZT within individual
patients over time – 1
Effectiveness of AZT within individual
patients over time – 2
The HIV population wthin an individual
evolves resistance to AZT – 1
• Reverse transcriptase enzyme is error prone
• HIV genome has highest spontaneous mutation rate
observed to date
• Large population of viral particles within host individual +
many generations within host + high mutation rate = many
mutations in the reverse transcriptase gene
• It is virtually guaranteed that some of these mutant forms
of reverse transcriptase will be less likely to be “fooled” by
AZT (i.e., less likely to use AZT during DNA synthesis)
HIV population within an individual evolves
resistance to AZT – 2
• Virions with such mutations will be more likely to
replicate, or replicate faster, (= survive and
reproduce) in the presence of AZT than will
virions without those mutations (= natural
selection), and the population of virions in the host
individual will become predominantly composed
of AZT resistant types (= evolution)
• AZT is the selective agent in the environment
• The HIV population in the host becomes adapted
to AZT
HIV population within an individual evolves
resistance to AZT – 3
• Mutations associated with AZT resistance are
often the same from patient to patient, and affect
the active site of the reverse transcriptase enzyme
• These mutations are heritable – can be passed on
to descendant virions
• If AZT treatment is stopped, the population of
HIV within an individual becomes less resistant to
AZT – resistance is non-adaptive (costly) in the
absence of AZT, perhaps because resistance
mutants have less efficient reverse transcription
Why is HIV fatal, or why does the immune
system fail to eliminate the virus?
• Immune system recognizes epitopes on the
surface of pathogens
• Epitopes (e.g., gp120) are encoded by viral
genome
• Because of error-prone replication, viral
epitopes are highly variable and evolve
continuously within a host individual during
an infection.
More about gp120
• Binds to CD4 protein and coreceptor on
host cell
• Recognized as an epitope by the host
immune system
• Mutations in the gp120 protein may help it
evade recognition by the immune system
Evolution of AZT resistance in a population
of HIV within an individual
Evolution of HIV gp120 coat protein coreceptor
binding site and epitope in a single HIV patient
Evolution of the gp120 protein
• Genetic difference between initial HIV population
and population after 11 years = 8%
• Human and chimp DNA vary by only about 2%
• “Rate of evolution” slows down after about 7
years – presumably because further mutation in
gp120 interferes with its ability to bind to host
cells
• However, by this time the host immune system has
collapsed beyond the point of recovery
An evolutionary arms race
• Within an individual host, HIV wins the
evolutionary arms race with the host
immune system
• The cost of this victory is the death of the
host and the death of the virions in the host
at the time
• Is this short-sighted from the point of view
of HIV?
Thinking on multiple levels
• So far we have been discussing selection at the
level of HIV populations within single host
individuals
• However, in order to succeed in the long term,
HIV must also be passed from person to person
• Thus, there must also be selection at the level of
transmission between hosts
• It may matter little if individual hosts die provided
that before they do so, the virus has infected
additional individuals. Besides, all host
individuals eventually die, anyway
Evidence that virulence and
infectiousness are positively correlated
• HIV-2 is both less virulent and less
infectious than HIV-1
Selection can happen on multiple
levels
• Selection at host-to-host level will favor mutations
that increase the rate of virus transmission from
host to host, even at the expense of killing
individual hosts (up to a point)
• But if host-to-host transmission is too effective
and the virus is too virulent, there is the risk of
extinction of the host (and the virus) species
• That would really be short-sighted of the virus
Why are some individuals
resistant to HIV?
• The most common coreceptor moleucle that
is used by HIV virions for attachment and
integration into host cells is CCR5
• Individuals carrying the CCR5-D32 allele
are resistant to HIV infection
• The frequency of the CCR5-D32 allele
varies among human populations
Frequency of CCR5-D32 allele in the Old World
More selection thinking
• HIV is a selective agent on human
populations – an example of natural
selection in humans
• An evolutionary arms race at the level of
species
• Will the CCR5-D32 allele increase in
frequency in human populations?
Where did HIV come from? – 1
• Spontaneous generation?
• HIV is similar in genome and life cycle to simian
immunodeficiency viruses – SIVs
• Nucleotide sequence comparisons of several HIV
and SIV strains suggest that SIVs have “jumped”
from monkeys and chimps to humans, and
subsequently evolved in HIV
• Evidence suggests that this has happened at least 4
times
Where did HIV come from? – 2
• HIV-1 is most closely related to SIV strains in
chimpanzees (3 origins)
• HIV-2 is similar to SIV strains in sooty
mangabeys – a monkey in west Africa
• Estimated date of movement of HIV-1 subgroup
M into humans is 1930 (± 15 yrs)
HIV family tree (phylogeny) – 1
HIV family tree (phylogeny) – 2
Dating the
common ancestor
of HIV-1 strains in
subgroup M
Why have HIV vaccines been unsuccessful?
• Vaccines consist of epitopes from killed or
weakened virions
• Most HIV epitopes are derived from the gp120
coat protein
• gp120 is highly variable
• Vaccines based on one (or a few) gp120 variant
may be ineffective against different HIV strains
• The high variability that enables HIV to resist host
immune systems also prevents development of a
successful vaccine.