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)