History says, don’t hope On this side of the grave But then, once in a lifetime

1. History says, don’t hope On this side of the grave But then, once in a lifetime The longed-for tidal wave Of justice can rise up And hope and history rhyme. Seamus Heaney, 1995 Nobel Laureate in Literature 1996 UNC commencement speaker “Voices from Lemnos”

2. The dawn of HIV A retrovirus causes AIDS In May 1983: doctors at the Institute Pasteur in France reported that they had isolated a new virus, which they suggested might be the cause of AIDS. Barre-Sinoussi F. … and Montagnier L. (1983), 'Isolation of a T-Lymphotropic retrovirus from a patient at risk for Acquired Immune Deficiency Syndrome (AIDS)', Science, May 20 In May 1983: doctors at the NIH in the US reported that a retrovirus virus related to Human T cell Leukemia virus was present in patients with AIDS. Gelman EP … and Gallo RC. (1983), “Proviral DNA of a retrovirus, human T-cell leukemia virus, in two patients with’AIDS, Science, May 20 January 1985 It becomes clear that LAV and HTLV-III are the same virus and The FDA licenses the first blood test for AIDS http://www.avert.org/his81_86.htm

3. But what is a retrovirus? In May 1983: doctors at the Institute Pasteur in France reported that they had isolated a new virus, which they suggested might be the cause of AIDS. Barre-Sinoussi F. … and Montagnier L. (1983), 'Isolation of a T-Lymphotropic retrovirus from a patient at risk for Acquired Immune Deficiency Syndrome (AIDS)', Science, May 20 In May 1983: doctors at the NIH in the US reported that a retrovirus virus related to Human T cell Leukemia virus was present in patients with AIDS. Gelman EP … and Gallo RC. (1983), “Proviral DNA of a retrovirus, human T-cell leukemia virus, in two patients with’AIDS, Science, May 20 January 1985 It becomes clear that LAV and HTLV-III are the same virus and The FDA licenses the first blood test for AIDS http://www.avert.org/his81_86.htm

4. But what is a retrovirus? http://www.avert.org/his81_86.htm

5. Retroviruses are part of a big family tree! THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

6. To understand this discovery We need to go back to the beginning http://www.avert.org/his81_86.htm

7. The central dogma-- Don’t forget this! DNA -> RNA -> Proteins

8. We called this step translation DNA -> RNA -> Proteins

9. How about this step? DNA -> RNA -> Proteins

10. It’s called Transcription DNA -> RNA -> Proteins

11. users.ugent.be/.../principles/centraldogma.html

12. As a general rule, one gene encodes one protein • Cellular machines are largely made up of proteins. • Proteins are made up of chains of amino acids. • The sequence of these amino acids are "encoded" in the cell's DNA. DNA is transcribed into RNA, which is then translated into protein. • When one gene is mutated, one protein (a machine) is affected (usually disabled).

13. This information flows requires machinery to carry it out DNA RNA Protein Transcription Translation RNA Polymerase Ribosome Replication DNA Polymerase Process in Black, Enzyme in Blue Enzymes are machines (most often made of only proteins) that catalyze a specific biochemical reaction

14. Transcription looks like this

15. Or in a slightly more detailed view

16. Many viruses have genomes like ours, composed of DNA

17. Other viruses have genomes that skip DNA

18. But retroviruses do things differently

19. But retroviruses do things differently RNA DNA RNA Retroviruses. CSHL Press Fig. 1-5

20. This part is BACKWARDS RNA DNA RNA Retroviruses. CSHL Press Fig. 1-5

21. How do they do that?? RNA DNA RNA Retroviruses. CSHL Press Fig. 1-5

22. Let’s take a closer look at the virus

23. Let’s take a closer look at the virus

24. How does HIV infect new people?

25. How does HIV infect new people?

26. How does HIV infect new people?

27. How does HIV infect new people?

28. Now let’s look closely to what happens when virus enters T cells

30. And if we look Even more closely

31. Retroviruses have stripped down genomes So they make good use of what they have

32. Let’s look at reverse transcriptase Science. 1992 Jun 26;256(5065):1783-90

33. It’s a distant relative of DNA polymerase! =Bacterial DNA polymersae

34. Encoded in pol are reverse transcriptase, RNAse H, and integrase!

35. Reverse transcriptase, the amazing enzyme that does it all

36. This will be important later!

37. This remarkable reversal of the central dogma was Simultaneously discovered by David Baltimore and Howard Temin And earned them the 1975 Nobel Prize in Medicine or Physiology David Baltimore Howard Temin

38. Now that the provirus is integrated in your DNA, It can generate new viruses

39. This involves transcription, Translation and processing of viral proteins

40. The Gag protein gets cleaved into pieces by an enzyme called a protease

41. The Gag protein gets cleaved into pieces by an enzyme called a protease

42. This cleavage is essential to make an infectious virion! Matrix Capsid Gag