An Evolutionary Story about HIV

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1 An Evolutionary Story about HIV Charles Goodnight University of Vermont Based on Freeman and Herron Evolutionary Analysis

2 The Aids Epidemic HIV has infected 60 million people. 1/3 have died so far

3 Worst Epidemics 1) Spanish influenza (1918) In the span of a few months killed 50 to 100 million 2) Black Death (1346) Over 5 years killed 30-40% of Europe s population Approximately 27 Million people 3) New World Small Pox (1520) Numbers are hard to estimate, decimated Native American Populations in both North and South America. AIDS has currently claimed 10 million lives, and it is estimated that it will claim 90 million lives by 2020.

4 HIV Virus HIV is a Retrovirus Genetic material 2 identical strands of RNA Reverse transcriptase transcribes RNA to DNA DNA makes viral proteins and viral RNA QuickTime and a GIF decompressor are needed to see this picture. Some important facts Humans do not have reverse transcriptase RNA retroviruses have very high mutation rates

5 HIV Virus Just to show we know a lot about their structure.

6 Three stages of an HIV infection

7 Immune system works, then fails HIV replicates rapidly T cells decline Immune system mobilizes HIV continues to replicate, T cells slowly decline T cell count, immune system collapses, HIV count increase accelerates

8 AZT and Reverse Transcriptase Azidothymidine QuickTime and a TIFF (LZW) decompressor are needed to see this picture. AZT works by replacing thymidine. When it does transcription stops.

9 Over time AZT fails As Therapy continues higher and higher doses of AZT are required in order to be effective

those that are resistant to AZT Increase population using AZT resistant variants RNA viruses

10 How to make an AZT resistant virus Reverse transcriptase Thought experiment Change enzyme so it does not bind to AZT What actually happens Use mutagen to generate viral variants Select those that are resistant to AZT Increase population using AZT resistant variants RNA viruses have high mutation rates Only AZT resistant forms can reproduce AZT resistant forms come to dominate.

11 Evolution as a Branching Process

12 The Evolution of HIV in an Individual

13 Summary to this Point After infection the patient becomes the population Selection favors variants that reproduce more quickly because: They avoid the immune system They are resistant to AZT More effectively invade and use T cells. When the immune system collapses so does selection to avoid it. At this level the health of the patient does not affect fitness Selection favors the here and now not the future! Selection favors more deadly viruses.

14 Evolution is short sighted Two variants of HIV (they interconvert by mutation) Use CCR5 as coreceptor (CCR5 is protein on one type of T cell) Use CXCR4 as coreceptor (CCR5 is protein on a different type of T cell) Early in infection CCR5 HIV predominate CCR5 using T cells divide faster giving a fitness advantage Late in infection CXCR4 HIV predominates Late in infection CXCR4 T cells start dividing much faster Short sighted because: CXCR4 HIV do not get transmitted to new hosts Attacking CXCR4 T cells speeds collapse of immune system

15 CCR5 HIV VS CXCR4 HIV In a healthy individual CCR5 HIV replicates faster than CXCR4 HIV A group was found infected with an HIV strain that only attacked CXCR4 T cells. Patients have lived much longer This should be good for fitness (more time to infect) This strain hasn t spread because it is MUCH less infective There appears to be a correlation between virulence and infectiveness Ultimately all hosts die. To persist the parasite must infect others hosts

16 Nobody really knows the answer to this. Genetic Resistance to HIV In humans the CCR5-Δ32 allele confers HIV resistance CCR5-Δ32 arose because: Neutral allele spread by Vikings? Conferred resistance to a European epidemic in the past?

17 Point of this Exercise HIV is a good model of evolution in action The four forces of evolution all contribute to the HIV phenotype Selection Faster reproducing strains dominate Mutation AZT resistance is a result of selection and mutation Migration Prevalence of HIV is a function of human migration Drift rare patients with low virulence forms of HIV, CCR5-Δ32 distribution in humans

18 Point of this Exercise Selection works on differences in fitness without regard to the future In HIV within a single host fitness differences are relatively simple In more complex systems this will not necessarily be true Selection on different aspects of the phenotype and different levels can interact to make the outcome of selection complex Within host selection favors increased virulence High virulence strains have higher transmissibility High virulence strains cause early host mortality.

19 Where did HIV come from? For this question we must reconstruct the past. First, Human Immunodeficiency Virus is similar to Simian Immunodeficiency Virus (SIV) Both are RNA retroviruses Life Cycles are similar Hosts are similar (humans, apes, monkeys) The logical conclusion HIV evolved from one of the SIVs. The question is which one?

21 Figure 1.21 This figure shows a phylogeny of HIV and SIV Note: HIV-2 derived from Sooty Mangabey SIV Sooty Mangabeys are hunted for food in Africa Stump tailed macaque SIV is actually from a captive monkey that caught it from a Sooty Mangabey HIV-1 derived from Chimpanzees Most recent common ancestor ~1930

22 Rapid Evolution and Short Term Phylogenies Phylogenetic analysis of 168 HIV-1 NC and p6 sequences from six mother-infant pairs; pairs B, C, D, E, F, and H. Each terminal node represents one sequence.

EVOLUTION. Reading. Research in my Lab. Who am I? The Unifying Concept in Biology. Professor Carol Lee. On your Notecards please write the following:

EVOLUTION. Reading. Research in my Lab. Who am I? The Unifying Concept in Biology. Professor Carol Lee. On your Notecards please write the following: Evolution 410 9/5/18 On your Notecards please write the following: EVOLUTION (1) Name (2) Year (3) Major (4) Courses taken in Biology (4) Career goals (5) Email address (6) Why am I taking this class?