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Bioe 109 EvolutionSummer 2009
Lecture 1: Part IIEvolution in action: the HIV virus
Class website: http://bio.classes.ucsc.edu/bioe109/
“Understanding Evolution” (http://evolution.berkeley.edu/evolibrary/) Check out this website—very informative and useful!
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……...
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?
Nothing in biology makes sense,except in the light of evolution!
Nothing in biology makes sense,except in the light of evolution!
Theodoseus Dobzhansky (1973)
The HIV/AIDS pandemic
Life expectancy in Botswana
What is HIV?
What is HIV?
• HIV is a retrovirus (i.e., RNA-based) with 9 genes
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)
The life cycle of HIV
Q: How does HIV cause AIDS?
Q: How does HIV cause AIDS?
A: By attacking a key player in our immune system – CD4 helper T-cells.
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!
The role of helper T cells in the immune response
The progression of an HIV infection
Changes in CD4 T-cell count during HIV infection
How does this lead to epidemic?
1. Infect host 2. Reproduce within host
3. Infect new host
Natural selection, AZT, and the HIV virus
• What is AZT?
Natural selection, AZT, and the HIV virus
• What is AZT?
• AZT (azidothymidine) is a base analogue.
Structure of azidothymidine
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.
How AZT blocks reverse transcriptase
Evolution of AZT resistance
Resistance evolves in the polymerase’s active site
Evolution of the HIV virus
How does natural selection work?
1. Variation is present or “generated” in population
How does natural selection work?
1. Variation is present or “generated” in population
2. Variation is heritable
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
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.
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!
There is no purpose or final goalthat evolution is trying to achieve!
Q. Why HIV is fatal?
Q. Why HIV is fatal?
A. “short-sightedness” of evolution
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
What about less harmful strains?
- e.g. Sydney blood bank cohort
What about less harmful strains?
-e.g. Sydney blood bank cohort
- Lower viral loads in body fluids
- Lower chance of getting into another host
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!
Resistance to AZT has evolved in all patients taking the drug (usually in ~6 months)!
• This is an example of parallel evolution.
How does HIV evolve so rapidly?
How does HIV evolve so rapidly?
1. High mutation rate
• HIV’s mutation rate is 106 higher than ours!
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.
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!
Evolution of HIV within an individual patient
Why are some people resistant to HIV?
The CCR5-32 allele confers resistance to HIV infection
Where did HIV come from?
Phylogeny of HIV-1 and related viruses
Where did HIV come from?
• HIV “jumped” to humans multiple times from different primate hosts.
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.
Dating the origin of HIV-1 in humans
Dating the origin of HIV-1 in humans
Dating the origin of HIV-1 in humans
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)
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