HIV/AIDS as a Microcosm for the Study of Evolution.

HIV/AIDS as a Microcosm for the Study of Evolution

Questions• What is HIV?• How does it “work”?• How does the immune system respond?• What is the course of a typical infection?• Why do drugs have limited effectiveness?• Why does the immune system not defeat

infection?• Why are some people resistant to HIV?• Where did HIV come from?• Why have HIV vaccines been unsuccessful?

What does this have to do with evolution?

• How populations change through time in response to changes in their environments — mutation, variation, natural selection, adaptation

• How new species come into being — biological diversity, phylogeny

HIV - History and impact

• First recognized 1981

• 60 million infected so far

• 1/3 have already died (5% of all deaths world-wide = 8,000/day)

• Estimated 90 million deaths by 2020

Prevalence of HIV-1 in adults age 15-45 (2001)

What is HIV?

• RNA retrovirus • Virion contains

– 2 identical RNA molecules– 3 proteins (including reverse transcriptase)

• Specific to two components of human immune system — T cells and macrophages

• Enters cells by attaching first to membrane protein CD4 and then to a second coreceptor protein (typically CCR5)

HIV life cycle in host cell

The course of a typical HIV infection within an individual

AZT: an anti-HIV drug

• AZT = azidothymidine, a thymine mimic• “Fools” reverse transcriptase into inserting AZT in

place of T when making DNA copies of viral RNA

• Stops reverse transcription, prevents viral replication (= reproduction)

• Causes serious side effects because DNA polymerase may also be “fooled” during replication of host cell genome

Effectiveness of AZT within individual patients over time – 1

Effectiveness of AZT within individual patients over time – 2

The HIV population wthin an individual evolves resistance to AZT – 1

• Reverse transcriptase enzyme is error prone

• HIV genome has highest spontaneous mutation rate observed to date

• Large population of viral particles within host individual + many generations within host + high mutation rate = many mutations in the reverse transcriptase gene

• It is virtually guaranteed that some of these mutant forms of reverse transcriptase will be less likely to be “fooled” by AZT (i.e., less likely to use AZT during DNA synthesis)

HIV population within an individual evolves resistance to AZT – 2

• Virions with such mutations will be more likely to replicate, or replicate faster, (= survive and reproduce) in the presence of AZT than will virions without those mutations (= natural selection), and the population of virions in the host individual will become predominantly composed of AZT resistant types (= evolution)

• AZT is the selective agent in the environment• The HIV population in the host becomes adapted

to AZT

HIV population within an individual evolves resistance to AZT – 3

• Mutations associated with AZT resistance are often the same from patient to patient, and affect the active site of the reverse transcriptase enzyme

• These mutations are heritable – can be passed on to descendant virions

• If AZT treatment is stopped, the population of HIV within an individual becomes less resistant to AZT – resistance is non-adaptive (costly) in the absence of AZT, perhaps because resistance mutants have less efficient reverse transcription

Why is HIV fatal, or why does the immune system fail to eliminate the virus?

• Immune system recognizes epitopes on the surface of pathogens

• Epitopes (e.g., gp120) are encoded by viral genome

• Because of error-prone replication, viral epitopes are highly variable and evolve continuously within a host individual during an infection.

More about gp120

• Binds to CD4 protein and coreceptor on host cell

• Recognized as an epitope by the host immune system

• Mutations in the gp120 protein may help it evade recognition by the immune system

Evolution of AZT resistance in a population of HIV within an individual

Evolution of HIV gp120 coat protein coreceptor binding site and epitope in a single HIV patient

Evolution of the gp120 protein

• Genetic difference between initial HIV population and population after 11 years = 8%

• Human and chimp DNA vary by only about 2%• “Rate of evolution” slows down after about 7

years – presumably because further mutation in gp120 interferes with its ability to bind to host cells

• However, by this time the host immune system has collapsed beyond the point of recovery

An evolutionary arms race

• Within an individual host, HIV wins the evolutionary arms race with the host immune system

• The cost of this victory is the death of the host and the death of the virions in the host at the time

• Is this short-sighted from the point of view of HIV?

Thinking on multiple levels• So far we have been discussing selection at the

level of HIV populations within single host individuals

• However, in order to succeed in the long term, HIV must also be passed from person to person

• Thus, there must also be selection at the level of transmission between hosts

• It may matter little if individual hosts die provided that before they do so, the virus has infected additional individuals. Besides, all host individuals eventually die, anyway

Evidence that virulence and infectiousness are positively correlated

• HIV-2 is both less virulent and less infectious than HIV-1

Selection can happen on multiple levels

• Selection at host-to-host level will favor mutations that increase the rate of virus transmission from host to host, even at the expense of killing individual hosts (up to a point)

• But if host-to-host transmission is too effective and the virus is too virulent, there is the risk of extinction of the host (and the virus) species

• That would really be short-sighted of the virus

Why are some individuals resistant to HIV?

• The most common coreceptor moleucle that is used by HIV virions for attachment and integration into host cells is CCR5

• Individuals carrying the CCR5-32 allele are resistant to HIV infection

• The frequency of the CCR5-32 allele varies among human populations

Frequency of CCR5-32 allele in the Old World

More selection thinking

• HIV is a selective agent on human populations – an example of natural selection in humans

• An evolutionary arms race at the level of species

• Will the CCR5-32 allele increase in frequency in human populations?

Where did HIV come from? – 1

• Spontaneous generation?• HIV is similar in genome and life cycle to simian

immunodeficiency viruses – SIVs• Nucleotide sequence comparisons of several HIV

and SIV strains suggest that SIVs have “jumped” from monkeys and chimps to humans, and subsequently evolved in HIV

• Evidence suggests that this has happened at least 4 times

Where did HIV come from? – 2

• HIV-1 is most closely related to SIV strains in chimpanzees (3 origins)

• HIV-2 is similar to SIV strains in sooty mangabeys – a monkey in west Africa

• Estimated date of movement of HIV-1 subgroup M into humans is 1930 (± 15 yrs)

HIV family tree (phylogeny) – 1

HIV family tree (phylogeny) – 2

Dating the common ancestor of HIV-1 strains in

subgroup M

Why have HIV vaccines been unsuccessful?

• Vaccines consist of epitopes from killed or weakened virions

• Most HIV epitopes are derived from the gp120 coat protein

• gp120 is highly variable• Vaccines based on one (or a few) gp120 variant

may be ineffective against different HIV strains• The high variability that enables HIV to resist host

immune systems also prevents development of a successful vaccine.