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”

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 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 But what is a retrovirus?

But what is a retrovirus?

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

To understand this discovery We 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 requires machinery to carry it out DNA RNA Protein Replication DNA Polymerase TranscriptionTranslation RNA PolymeraseRibosome 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

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 genomes So they make good use of what they have

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

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 was Simultaneously discovered by David Baltimore and Howard Temin And earned them the 1975 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 pieces by an enzyme called a protease

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

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