Why study evolution?

Best conceptual framework for understandingorigins of biodiversity

Adaptations that allow organisms to exploit their environment

Self discoveryKeystone of biology (including human health)

Lecture: HIV

I. Motivation

What can we learn when we apply evolutionary principles to our understanding of the of the HIV epidemic?? Can we use HIV to introduce us to evolutionary principles

Natural SelectionMutationGene FlowDescent with Modification

II. Prevalence & Effect

Life expectancy in Botswana

HIV is a natural selectiveagent

III. Basic Biology of HIV and Human Immunoresponse

Infectious stage

Helper T-cell

Reverse transcriptase

11. HIV replication = T-cell death

*

IV. HIV Treatment

How AZT blocks reverse transcriptase

pyrimidine

V. Evolution of HIV in Host

AZT is a selective agent On HIV

Needed to prevent replication in t-tubes

Can we predict the changes in Reverse Transcriptase* using

evolutionary principles??

*due to AZT

HIV Contributes to Collapse of Immune System in 3 Ways:

1. Continuous evolution of HIV proteins used by human immune system to recognize HIV

2. Evolution towards more and more aggressive replication

3. HIV often evolve to infect different immune cells (naïve T cells) using different immune cell receptor proteins

Years since patient became HIV Positive

Evolution at gp120 locus

HIV strains evolve to become more competitive with other viruses

HIV evolves to recognize the CXCR4 receptor on Naïve helper T cells

What therapy is there for a continuously evolving disease??

A therapy that requires HIV to evolve at many sequences through manymutations

HIV-1 interacts with a cell-surface receptor, primarily CD4, and through conformational changes becomes more closely associated with the cell through interactions with other cell-surface molecules, such as the chemokine receptors CXCR4 and CCR5.

VI. Evolution of the Host, Evidence for Genetic Variation for Resistance

Genetic variationIn Africa for Resistance to HIV

Deletion in CCR5 locus

Sex workers in Kenya having a C instead of a T at position 868 for CD4 have resistance to HIV

Two loci in human populations confer resistance to HIV

VII. Evolution of Human Specific HIVMultiple evolution of HIV

Group M HIV-1 Strains

Innocent

Guilty

Evidence

Why are humans susceptible to HIV??

Perhaps constrained by past evolutionary history

TRIM5alpha = antiviral protein

at position 332 ofprotein glutamineinstead of arginine

VIII. HIV is a good model to start us thinking in evolutionary terms:

1. Selective agents on host and disease

2. Source or origin of disease

3. Strategies to combat HIV

Highlights evolutionary theory:

Natural selectionMutationGene FlowDescent with ModificationConstraints from past evolution

?? Why does HIV kill its host??