Download (1983), “Proviral DNA of a retrovirus, human T

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”
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
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
But what is
a retrovirus?
http://www.avert.org/his81_86.htm
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
To understand this discovery
We need to go back to the beginning
http://www.avert.org/his81_86.htm
The central dogma-Don’t forget this!
DNA -> RNA -> Proteins
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
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).
This information flow requires
machinery to carry it out
Transcription
DNA
RNA Polymerase
Translation
RNA
Ribosome
Protein
Replication
DNA Polymerase
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
But retroviruses do things differently
RNA
DNA
RNA
Retroviruses. CSHL Press Fig. 1-5
This part is “BACKWARDS”
RNA
DNA
RNA
17% of our genome encodes retro-transposons!!
Retroviruses. CSHL Press Fig. 1-5
How do they do that??
RNA
DNA
RNA
Retroviruses. CSHL Press Fig. 1-5
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
And
Even more closely
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!!
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
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
Structure of the HIV-1 gag-pol frameshift element
Watts JM, Nature. 2009 Aug 6;460(7256):711-6
The HIV Virion
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom
Retroviruses have stripped down genomes
So 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!
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 BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom
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
Matrix
Capsid