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Bioe 109 EvolutionSummer 2009
Lecture 1: Part IIEvolution in action: the HIV virus
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Class website: http://bio.classes.ucsc.edu/bioe109/
“Understanding Evolution” (http://evolution.berkeley.edu/evolibrary/) Check out this website—very informative and useful!
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Some of the worst epidemics in human history
•Influenza (1918) 50-100 million deaths worldwide
•Black death (1347-1352) ~100 million deaths worldwide
•New world small pox (~1520)
•Plague
•Malaria, TB, Cholera, Polio, SARS, bird flu and the latest H1N1 flu (???)
•AIDS (1981-to date) ~25 million deaths so far andcounting……...
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HIV: a case study
• What is HIV?
• Why does HIV kill people?
• Why did early AIDS treatments proved ineffective in the long run?
• Why are some people resistant to becoming infected or to progress to disease once they are infected?
• Where did HIV come from?
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Nothing in biology makes sense,except in the light of evolution!
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Nothing in biology makes sense,except in the light of evolution!
Theodoseus Dobzhansky (1973)
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The HIV/AIDS pandemic
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Life expectancy in Botswana
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What is HIV?
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What is HIV?
• HIV is a retrovirus (i.e., RNA-based) with 9 genes
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What is HIV?
• HIV is a retrovirus (i.e., RNA-based) with 9 genes
• is diploid (i.e., has 2 copies of each RNA strand)
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The life cycle of HIV
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Q: How does HIV cause AIDS?
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Q: How does HIV cause AIDS?
A: By attacking a key player in our immune system – CD4 helper T-cells.
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Infect CD4 helper T cells
Destruction of infected cells
Immune system is weakened
Secondary infections
Death
Q: How does HIV cause AIDS?
A: By attacking a key player in our immune system – CD4 helper T-cells.
Battle plan!
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The role of helper T cells in the immune response
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The progression of an HIV infection
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Changes in CD4 T-cell count during HIV infection
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How does this lead to epidemic?
1. Infect host 2. Reproduce within host
3. Infect new host
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Natural selection, AZT, and the HIV virus
• What is AZT?
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Natural selection, AZT, and the HIV virus
• What is AZT?
• AZT (azidothymidine) is a base analogue.
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Structure of azidothymidine
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Natural selection, AZT, and the HIV virus
• What is AZT?
• AZT (azidothymidine) is a base analogue.
• Incorporation of AZT (instead of T) by reverse transcriptase halts replication.
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How AZT blocks reverse transcriptase
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Evolution of AZT resistance
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Resistance evolves in the polymerase’s active site
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Evolution of the HIV virus
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How does natural selection work?
1. Variation is present or “generated” in population
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How does natural selection work?
1. Variation is present or “generated” in population
2. Variation is heritable
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How does natural selection work?
1. Variation is present or “generated” in population
2. Variation is heritable
3. Some individuals are better at surviving and/or reproducing under given selective pressure
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How does natural selection work?
1. Variation is present or “generated” in population
2. Variation is heritable
3. Some individuals are better at surviving and/or reproducing under given selective pressure
4. Genetic composition of the population changesover time.
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How does natural selection work?
1. Variation is present or “generated” in population
2. Variation is heritable
3. Some individuals are better at surviving and/or reproducing under given selective pressure
4. Genetic composition of the population changesover time.
This is the process of adaptation by natural selection!
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There is no purpose or final goalthat evolution is trying to achieve!
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Q. Why HIV is fatal?
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Q. Why HIV is fatal?
A. “short-sightedness” of evolution
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Why HIV is fatal?• By changing epitopes rapidly, the virus evades host
immune system.
• Can evolve aggressive replication
• Can evolve to infect naïve T cells accelerating thecollapse of host immune system
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What about less harmful strains?
- e.g. Sydney blood bank cohort
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What about less harmful strains?
-e.g. Sydney blood bank cohort
- Lower viral loads in body fluids
- Lower chance of getting into another host
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What about less harmful strains?
-e.g. Sydney blood bank cohort
- Lower viral loads in body fluids
-Lower chance of getting into another host
They are rare!
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Resistance to AZT has evolved in all patients taking the drug (usually in ~6 months)!
• This is an example of parallel evolution.
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How does HIV evolve so rapidly?
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How does HIV evolve so rapidly?
1. High mutation rate
• HIV’s mutation rate is 106 higher than ours!
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How does HIV evolve so rapidly?
1. High mutation rate
• HIV’s mutation rate is 106 higher than ours!
2. Short generation time
• 1 year 300 viral generations.
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How does HIV evolve so rapidly?
1. High mutation rate
• HIV’s mutation rate is 106 higher than ours!
2. Short generation time
• 1 year 300 viral generations.
10 years of viral 2-3 x 106 years of evolution human evolution!
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Evolution of HIV within an individual patient
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Why are some people resistant to HIV?
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The CCR5-32 allele confers resistance to HIV infection
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Where did HIV come from?
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Phylogeny of HIV-1 and related viruses
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Where did HIV come from?
• HIV “jumped” to humans multiple times from different primate hosts.
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Where did HIV come from?
• HIV “jumped” to humans multiple times from different primate hosts.
• These inter-species transfers of infectious diseases are called zoonoses.
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Dating the origin of HIV-1 in humans
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Dating the origin of HIV-1 in humans
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Dating the origin of HIV-1 in humans
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What did we learn today?
• HIV life cycle and progression of AIDS
• HIV epidemic
• Natural selection in presence of AZT
• How natural selection works
• “short-sightedness” of evolution
• tracing back origins of HIV virus (phylogenetics)