Download Lecture 2 Evolution in action: the HIV virus

Lecture 2
Evolution in action: the HIV virus
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.
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
The life cycle of HIV
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
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 ≅
evolution
2-3 x 106 years of
human evolution!
Evolution of HIV within an individual patient
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.
• Inter-species transfers of infectious
diseases are called zoonoses.
Other examples of zoonoses…
Malaria (P. falciparum)
Cholera
Plague
Dengue fever
H1N1 swine flu
Ebola
SARS
West Nile virus
Creutzfeldt-Jakob disease
Marburg fever
Leishmaniasis
Hantavirus
Toxoplasmosis
Rabies
Ringworms
Cowpox
Lyme disease
Yellow fever
Human Plasmodium falciparum
Chimpanzee Plasmodium spp.
see Rich et al. Proc. Natl.
Acad. Sci. U.S.A. 106: 14902
Dating the origin of HIV-1 in humans
Dating the origin of HIV-1 in humans
Dating the origin of HIV-1 in humans
Q: Why is HIV infection usually fatal?
Q: How do viruses achieve
reproductive success?
Q: How do viruses achieve
reproductive success?

1. Infect host
Q: How do viruses achieve
reproductive success?

1. Infect host
2. Reproduce
within host
Q: How do viruses achieve
reproductive success?

1. Infect host

2. Reproduce
within host
3. Infect new host
Q: How do viruses achieve
reproductive success?

1. Infect host

2. Reproduce
within host
3. Infect new host
Strategy 1: Reproduce rapidly within host
Strategy 1: Reproduce rapidly within host
↓
↑ Chance of infecting new host
↓ Host viability
Strategy 1: Reproduce rapidly within host
↓
↑ Chance of infecting new host
↓ Host viability
Strategy 2: Reproduce slowly within host
Strategy 1: Reproduce rapidly within host
↓
↑ Chance of infecting new host
↓ Host viability
Strategy 2: Reproduce slowly within host
↓
↓ Chance of infecting new host
↑ Host viability
Q: Why is HIV infection usually fatal?
Q: Why is HIV infection usually fatal?
A: Because the virus is “shortsighted”
Q: Why is HIV infection usually fatal?
A: Because the virus is “shortsighted”
- lethal strains predominate because of a shortterm advantage in survival and reproduction.
Q: Why has a vaccine for HIV-1 not
been successfully developed?
Q: Why has a vaccine for HIV-1 not
been successfully developed?
A1: Because the virus evolves very
rapidly.
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.
Distribution of HIV-1 major clades
The CCR5-Δ32 allele confers resistance to
HIV infection