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. A retrovirus causes AIDS
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

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

4. But what is a retrovirus?

5. Retroviruses are part of a big family tree!
Causes Leukemia!
Causes No Disease!
Lentiviruses do not cause cancer, and they establish chronic infections that result in a long incubation followed by a chronic symptomatic disease.
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

6. To understand this discovery We need to go back to the beginning

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

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

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

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

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

12. one gene encodes one protein -but really one function- (usually!)
As a general rule,
one gene encodes one protein
-but really one function- (usually!)
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. DNA RNA Protein This information flow 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
17% of our genome encodes retro-transposons!!
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. A detailed look at HIV entry
gp120 and gp41 made as a precursor protein
that is cleaved in the trans-Golgi network
Cellular Microbiology (2012) 14(8), 1183–1192

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

31. Retroviruses have stripped down genomes
So they make good use of what they have
Primer Binding Site for tRNA primer
PPT: polypurine tract (RNAse H resistant)
— primes + strand synthesis
LTR: long terminal repeat
— viral integration
— transcription from 5’ LTR
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

32. A close look at retroviral replication
Comptes Rendus Biologies Volume 325, Issue 1, January 2002, Pages 17–23

33. Template switching
results in
recombination of
viral genomes and
increased HIV1
diversity

34. HIV Viral Integration into our genome
Cold Spring Harb Perspect Med 2012;2:a006890

35. HIV Viral Integration into our genome
2 cool facts:
Lentiviruses can
Integrate in non-dividing
Cells, because the genome
Can be transported into the
nucleus
Our genomes contain
remnants of retroviruses,
providing a history of 40
million years of primate evolution.
Without deletion, these would represent 40% of genome!!

36. Retroviruses have stripped down genomes
So they make good use of what they have
Encoded by
FL transcript
-1 translation frameshift 5% of time
Bicistronic mRNA
Vif, vpr, tat, rev, nef all encoded by other mRNAs
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

37. Structure of the HIV-1 gag-pol frameshift element
Watts JM, Nature Aug 6;460(7256):711-6

38. The HIV Virion
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

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

40. Let’s look at reverse transcriptase
Science Jun 26;256(5065):

41. It’s a distant relative of DNA polymerase!

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

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

44. This will be important later!

45. 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

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

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

48. The Gag protein gets cleaved into pieces
by an enzyme called a protease
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

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

50. The Gag protein gets cleaved into pieces
by an enzyme called a protease
Matrix
Capsid
Gag