1. Bioe 109 Evolution Summer 2009 Lecture 1: Part II Evolution in action: the HIV virus

2. Class website: http://bio.classes.ucsc.edu/bioe109/ “Understanding Evolution” (http://evolution.berkeley.edu/evolibrary/) Check out this website—very informative and useful!

3. 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 and counting……...

4. 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?

5. Nothing in biology makes sense, except in the light of evolution!

6. Nothing in biology makes sense, except in the light of evolution! Theodoseus Dobzhansky (1973)

7. The HIV/AIDS pandemic

8. Life expectancy in Botswana

9. What is HIV?

10. HIV is a retrovirus (i.e., RNA-based) with 9 genes

11. 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)

12. The life cycle of HIV

13. Q: How does HIV cause AIDS?

14. A: By attacking a key player in our immune system – CD4 helper T-cells.

15. 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!

16. The role of helper T cells in the immune response

17. The progression of an HIV infection

18. Changes in CD4 T-cell count during HIV infection

19. How does this lead to epidemic? 1. Infect host2. Reproduce within host 3. Infect new host 

20. Natural selection, AZT, and the HIV virus What is AZT?

21. Natural selection, AZT, and the HIV virus What is AZT? AZT (azidothymidine) is a base analogue.

22. Structure of azidothymidine

23. 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.

24. How AZT blocks reverse transcriptase

25. Evolution of AZT resistance

26. Resistance evolves in the polymerase’s active site

27. Evolution of the HIV virus

28. How does natural selection work? 1. Variation is present or “generated” in population

29. How does natural selection work? 1. Variation is present or “generated” in population 2. Variation is heritable

30. 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

31. 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 changes over time.

32. 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 changes over time. This is the process of adaptation by natural selection!

34. There is no purpose or final goal that evolution is trying to achieve!

35. Q. Why HIV is fatal?

36. A. “short-sightedness” of evolution

37. 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 the collapse of host immune system

39. What about less harmful strains? - e.g. Sydney blood bank cohort

40. What about less harmful strains? -e.g. Sydney blood bank cohort - Lower viral loads in body fluids - Lower chance of getting into another host

41. 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!

42. Resistance to AZT has evolved in all patients taking the drug (usually in ~6 months)! This is an example of parallel evolution.

43. How does HIV evolve so rapidly?

44. 1. High mutation rate HIV’s mutation rate is 10 6 higher than ours!

45. How does HIV evolve so rapidly? 1. High mutation rate HIV’s mutation rate is 10 6 higher than ours! 2. Short generation time 1 year  300 viral generations.

46. How does HIV evolve so rapidly? 1. High mutation rate HIV’s mutation rate is 10 6 higher than ours! 2. Short generation time 1 year  300 viral generations. 10 years of viral  2-3 x 10 6 years of evolution human evolution!

47. Evolution of HIV within an individual patient

48. Why are some people resistant to HIV?

49. The CCR5-  32 allele confers resistance to HIV infection

50. Where did HIV come from?

51. Phylogeny of HIV-1 and related viruses

52. Where did HIV come from? HIV “jumped” to humans multiple times from different primate hosts.

53. 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.

55. Dating the origin of HIV-1 in humans

58. 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)