History says, don’t hopeOn this side of the graveBut then, once in a lifetimeThe longed-for tidal waveOf justice can rise upAnd hope and history rhyme.

Seamus Heaney,1995 Nobel Laureate in Literature1996 UNC commencement speaker “Voices from Lemnos”

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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 andThe FDA licenses the first blood test for AIDS

The dawn of HIVA retrovirus causes AIDS

http://www.avert.org/his81_86.htm

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 andThe FDA licenses the first blood test for AIDS

But what isa retrovirus?

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But what isa retrovirus?

THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom

Retroviruses are part of a big family tree!

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To understand this discoveryWe need to go back to the beginning

DNA -> RNA -> Proteins

The central dogma--Don’t forget this!

We called this step translation

DNA -> RNA -> Proteins

How about this step?

DNA -> RNA -> Proteins

It’s called Transcription

DNA -> RNA -> Proteins

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

• 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).

As a general rule, one gene encodes one protein

This information flows requiresmachinery to carry it out

DNA RNA Protein

ReplicationDNA Polymerase

Transcription Translation

RNA Polymerase Ribosome

Process in Black, Enzyme in Blue

Enzymes are machines (most often made of only proteins) that catalyze a specific biochemical reaction

Transcription looks like this

Or in a slightly more detailed view

Many viruses have genomes like ours, composed of DNA

Other viruses have genomes that skip DNA

But retroviruses do things differently

Retroviruses. CSHL Press Fig. 1-5

RNA

DNA

RNA

But retroviruses do things differently

Retroviruses. CSHL Press Fig. 1-5

RNA

DNA

RNA

This part is BACKWARDS

Retroviruses. CSHL Press Fig. 1-5

RNA

DNA

RNA

How do they do that??

Let’s take a closer look at the virus

Let’s take a closer look at the virus

How does HIV infect new people?

How does HIV infect new people?

How does HIV infect new people?

How does HIV infect new people?

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

And if we look Even more closely

Retroviruses have stripped down genomesSo they make good use of what they have

Let’s look at reverse transcriptase

Science. 1992 Jun 26;256(5065):1783-90

It’s a distant relative of DNA polymerase!

=Bacterial DNA polymersae

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

Reverse transcriptase, the amazing enzyme that does it all

This will be important later!

This remarkable reversal of the central dogma wasSimultaneously discovered by David Baltimore and Howard TeminAnd earned them the1975 Nobel Prize in Medicine or Physiology

David Baltimore

Howard Temin

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

This involves transcription,Translation and processing of viral proteins

The Gag protein gets cleaved into piecesby an enzyme called a protease

The Gag protein gets cleaved into piecesby an enzyme called a protease

Gag Capsid

Matrix

This cleavage is essential to make an infectious virion!