Lecture 2 Evolution in action: the HIV virus

Peter and Rosemary Grant

Barry Sinervo

The HIV/AIDS pandemic

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 ≅ 2-3 x 106 years of evolution human evolution!

Evolution of HIV within an individual patient

Where did HIV come from?

Phylogeny of HIV-1 and related viruses

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) 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

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?

1. Infect host

à

Q: How do viruses achieve reproductive success?

1. Infect host 2. Reproduce within host

à

Q: How do viruses achieve reproductive success?

1. Infect host 2. Reproduce within host

3. Infect new host

à à

Q: How do viruses achieve reproductive success?

Q: How do viruses achieve reproductive success?

1. Infect host 2. Reproduce within host

3. Infect new host

à à

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

Strategy 2: Reproduce slowly within host

↓ ↑ Chance of infecting new host ↓ Host viability

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

Q: Why is HIV infection usually fatal?

Q: Why is HIV infection usually fatal? A: Because the virus is “short- sighted”

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.

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