lecture 2 evolution in action: the hiv virusbio.classes.ucsc.edu/bio175/lectures/2_hiv.pdf · q:...
TRANSCRIPT
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Lecture 2 Evolution in action: the HIV virus
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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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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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The life cycle of HIV
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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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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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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.
• Inter-species transfers of infectious diseases are called zoonoses.
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Other examples of zoonoses…
Malaria (P. falciparum) Marburg fever Cholera Leishmaniasis Plague Hantavirus Dengue fever Toxoplasmosis H1N1 swine flu Rabies Ebola Ringworms SARS Cowpox West Nile virus Lyme disease Creutzfeldt-Jakob disease Yellow fever
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Human Plasmodium falciparum
Chimpanzee Plasmodium spp.
see Rich et al. Proc. Natl. Acad. Sci. U.S.A. 106: 14902
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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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Q: Why is HIV infection usually fatal?
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Q: How do viruses achieve reproductive success?
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1. Infect host
Q: How do viruses achieve reproductive success?
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1. Infect host 2. Reproduce within host
Q: How do viruses achieve reproductive success?
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1. Infect host 2. Reproduce within host
3. Infect new host
Q: How do viruses achieve reproductive success?
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Q: How do viruses achieve reproductive success?
1. Infect host 2. Reproduce within host
3. Infect new host
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Strategy 1: Reproduce rapidly within host
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Strategy 1: Reproduce rapidly within host
↓ ↑ Chance of infecting new host ↓ Host viability
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Strategy 1: Reproduce rapidly within host
Strategy 2: Reproduce slowly within host
↓ ↑ Chance of infecting new host ↓ Host viability
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Strategy 1: Reproduce rapidly within host
Strategy 2: Reproduce slowly within host
↓
↓
↑ Chance of infecting new host ↓ Host viability
↓ Chance of infecting new host ↑ Host viability
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Q: Why is HIV infection usually fatal?
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Q: Why is HIV infection usually fatal?
A: Because the virus is “short- sighted”
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Q: Why is HIV infection usually fatal?
A: Because the virus is “short- sighted”
- lethal strains predominate because of a short-term advantage in survival and reproduction.
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Q: Why has a vaccine for HIV-1 not been successfully developed?
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Q: Why has a vaccine for HIV-1 not been successfully developed?
A1: Because the virus evolves very rapidly.
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Q: Why has a vaccine for HIV-1 not been successfully developed?
A1: Because the virus evolves very rapidly.
A2: Because of HIV-1 strain diversity.
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Distribution of HIV-1 major clades
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The CCR5-Δ32 allele confers resistance to HIV infection