1. Unit 04 Population Dynamics HIV and humans

2. Building complexity From a single cell to a population… Single Cells Population of viruses Population of humans

3. Single Cells How matter flows from cells through other cells How energy flows from the sun through plant and animal cells How cells respond to changes in their environment and reproduce

4. Genomics and Proteomics –Genomics is the science of studying whole genomes.

5. Proteomics –Success in genomics has given rise to proteomics, The systematic study of the full set of proteins found in organisms.

7. What is a Population? “A group of interacting individuals belonging to one species and living in the same geographic area at the same time.” Population of viruses in a single person at the same time Population of humans in the same area at the same time

8. Population Dynamics How do we study populations? –How do they grow? –How can we describe them? How do populations respond to the environment?

9. HIV/AIDS

10. HIV Disease progression

11. Animal Viruses –Viruses that infect animals are common causes of disease. –From Medical Virology 4th Ed. By White and Fenner

12. –The reproductive cycle of an enveloped virus Simplified Viral Reproductive Cycle Influenza virus

13. HIV, the AIDS Virus –HIV is a retrovirus. A retrovirus is an RNA virus that reproduces by means of a DNA molecule. It copies its RNA to DNA using reverse transcriptase

14. –How HIV reproduces inside a CD4 + T lymphocyte (T cell) Integrase Protease Glycoproteins gp120, gp41

15. –AIDS is Acquired immune deficiency syndrome. The disease caused by HIV infection. Treated with many classes of drugs: –Reverse transcriptase inhibitors (AZT, ddC,…) –Protease inhibitors –Integrase inhibitors –Fusion inhibitors http://www.youtube.com/ watch?v=RO8MP3wMv qg

16. HIV drug resistance: How does this happen? 2537 patients with HIV in the UK from 1996-2003. None had received anti- retrovirals before they joined the study. They were then placed on combination anti-retroviral therapy.

17. HIV drug resistance Initial ideas What would the genomes of a population of HIV viruses look like at each of the following time points: Time 0 – before anti-HIV drug is taken Time 1 – when the anti-HIV drug is taken Time 2 – some time later while the anti- HIV drug is still being taken.

18. The Darwinian View of Life The evolutionary view of life came into focus in 1859 when Charles Darwin published The Origin of Species.

19. –Darwin’s book developed two main points: Descent with modification Natural selection EVOLUTION The Mechanism of EVOLUTION

20. Natural Selection –Darwin was struck by the diversity of animals on the Galápagos Islands. – He thought of adaptation to the environment and the origin of new species as closely related processes. As populations separated by a geographic barrier adapted to local environments, they became separate species.

21. –Fourteen species of Galápagos finches have beak shapes adapted to suit their environments.

22. Darwin’s Inescapable Conclusion –Fact 1: Potential for overproduction and competition for existence –Fact 2: Individual variation –The inescapable conclusion: Unequal reproductive success Darwin called this process natural selection. The result of natural selection is adaptation.

24. Observing Artificial Selection Artificial selection is the selective breeding of domesticated plants and animals by humans.

25. Observing Natural Selection –There are many examples of natural selection in action. The development of antibiotic-resistant bacteria is one. Tuberculosis - MDR-TB - XDR-TB Staphylcoccus aureus (staph) - CA-MRSA

26. Darwin’s Inescapable Conclusion –Fact 1: Potential for overproduction and competition for existence –Fact 2: Individual variation –The inescapable conclusion: Unequal reproductive success Darwin called this process natural selection. The result of natural selection is evolution when a population has adapted to its environment. Evidence for HIV?

27. How do we study overproduction and struggle for existence? Look to Ecology –Ecology Is the scientific study of the interactions between organisms and their environments.

28. A Hierarchy of Interactions

29. Population Growth Models –Two models, the exponential growth model and the logistic growth model, will help us understand population growth. –The growth rate Is the change in population size over time

30. The Exponential Growth Model: The Ideal of an Unlimited Environment –The exponential growth model Describes the rate of expansion of a population under ideal, unregulated conditions. –Enough food and resources –Waste is washed or taken away or not significant Copyright © 2007 Pearson Education Inc., publishing as Pearson Benjamin Cummings

31. Figure 18.17

32. The Logistic Growth Model: The Reality of a Limited Environment –In nature, a population may grow exponentially for a while, but eventually one or more environmental factors will limit its growth. –Population-limiting factors restrict population growth. Copyright © 2007 Pearson Education Inc., publishing as Pearson Benjamin Cummings

33. –A comparison of the logistic growth model and the exponential growth model –Carrying capacity Is the number of individuals in a population that the environment can just maintain with no net increase or decrease.

34. HIV Disease progression: Modified Logistic Growth Model HIV can reproduce over a billion times a day. It is in a constant struggle for existence with the immune system

35. HIV drug resistance: How does this happen? 2537 patients with HIV in the UK from 1996-2003. None had received anti- retrovirals before they joined the study. They were then placed on combination anti-retroviral therapy.

36. Darwin’s Inescapable Conclusion –Fact 1: Potential for overproduction and competition for existence –Fact 2: Individual variation –The inescapable conclusion: Unequal reproductive success Darwin called this process natural selection. The result of natural selection is evolution when a population has adapted to its environment. Evidence for HIV?

37. Random Mutations in the genome are the basis of individual variation Base substitution –Silent mutation –Missense mutation –Nonsense mutation Insertion or deletion –Reading frame shift They occur at random by –Errors in DNA replication by enzymes –Exposure to mutagens (UV, chemicals, etc…) Mutations can be beneficial, harmless, or harmful

38. –In 2003, the Food and Drug Administration Approved the drug gefinitib for the treatment of lung cancer. Gefinitib blocks signaling from a growth factor receptor (a receptor that signals the cell to grow and divide!) found in abundance on some lung cancer cells. –Unfortunately, gefinitib is ineffective for many patients. Copyright © 2007 Pearson Education Inc., publishing as Pearson Benjamin Cummings An Example of Mutations that have an effect on drug response in humans.

39. –A 2004 study found that genetic differences among patients affected their response to the drug, Pre-existing individual variation in a population of humans affects their ability to respond to the drug.

40. Figure 10.1 How does the anti-HIV drug AZT work?

41. How do mutations cause drug resistance? http://www.cabm.rutgers.edu/~kalyan/RT_imgs/index.html –Dr. Kalyan Das at Rutgers University

42. How do mutations in the genome cause resistance?

44. Time 0: Overproduction and pre-existing individual variation caused by random mutations Natural Selection at work Time 2: Population has evolved Time 1: Struggle for existence: Environmental Selection

45. HIV drug resistance! How?? 1.Large amount of offspring HIV replicates over a billion times a day 2.Reverse transcriptase (RT) is error-prone! About 50% of HIV DNA transcripts made by RT contain at least one mistake (mutation) at random. 3.Random mutation is heritable 4.Mutants are better able to reproduce in selective environment 5.Population adapts to change in environment, resulting in a different population = evolution Overproduction Heritable Individual variation Struggle for existence

46. Microbe evolution TODAY http://www.youtube.com/watch?v= 34GeUa7RzvY http://www.youtube.com/watch?v= W-WumllRPLI&feature=related Video 1: HIV Evolution on PBS (7:30 min) Video 2: MDR-TB Evolution on PBS (9 min)