I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one,...
-
Upload
theodora-simmons -
Category
Documents
-
view
229 -
download
1
Transcript of I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one,...
![Page 1: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/1.jpg)
I guess you think you know this story.You don’t. The real one’s much more gory.The phoney one, the one you knowWas cooked up years and years ago.”
Roald Dahl“Revolting Rhymes”
![Page 2: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/2.jpg)
http://www.avert.org/his81_86.htm
Reverse transcriptase inhibitors were a Major breakthrough in treating AIDS
![Page 3: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/3.jpg)
http://www.avert.org/his81_86.htm
Even as new uses for AZT were reported…
January 1993
A study, ACTG 076, showed that AZT reduced by two thirds the risk of HIV transmission from infected mothers to their babies.
Connor E.D. et al. (1994) 'Reduction of maternal-infant transmission of Human Immunodeficiency Virus type 1 with zidovudine treatment' ,The New England Journal of Medicine, Vol. 331:1173-1180, November 3, No. 18
![Page 4: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/4.jpg)
http://www.avert.org/his81_86.htm
And AZT and other RT inhibitors started to level off the rise in AIDS cases
![Page 5: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/5.jpg)
New RT inhibitors bought some time but by the mid 1990s resistance to AZT and other RT inhibitors was a serious problem
some people with AIDS already had resistance to AZT even though they themselves had never taken the drug.
We needed a new approach--what can TB treatmentteach us about how we might approach things?
![Page 6: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/6.jpg)
We need a new drug target
![Page 7: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/7.jpg)
Enzymes make good drug targetswhat other enzymes does HIV use?
![Page 8: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/8.jpg)
Let’s look here!
![Page 9: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/9.jpg)
The Gag protein gets cleaved into piecesby an enzyme called a protease
![Page 10: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/10.jpg)
Gag Capsid
Matrix
The Gag protein gets cleaved into piecesby an enzyme called a protease
![Page 11: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/11.jpg)
You want a drug that fits into the “active site”Where the enzyme does its work
Copyright ©2006 by the National Academy of Sciences
Das, Amit et al. (2006) Proc. Natl. Acad. Sci. USA 103, 18464-18469
![Page 12: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/12.jpg)
Retroviruses. CSHL Press Fig. 13-15
You start with its natural substrate:a polypeptide backbone and the site of protease cleavage (arrow)
![Page 13: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/13.jpg)
Retroviruses. CSHL Press Fig. 13-15
You look for things with a similar shapeIn part of the molecule
![Page 14: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/14.jpg)
www.clubbiotech.at/ blundell.htm
These can fit into the “active site” and stop up the workspreventing the enzyme from doing its work
![Page 15: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/15.jpg)
The “protease inhibitors” that pass further tests become drugs!
December 1995The FDA approved the first of a potent new family of anti-AIDS medications. The drug saquinavir belonged to a class of drugs called protease inhibitors.
![Page 16: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/16.jpg)
December 1995The FDA approved the first of a potent new family of anti-AIDS medications. The drug saquinavir belonged to a class of drugs called protease inhibitors.
Do you want to use “protease inhibitors” alone?
![Page 17: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/17.jpg)
Retroviruses. CSHL Press Fig. 13-18, Modified from Gulick et al. 1997
Combination therapy worked well
The baseline median viral RNA level in this study was 41,000 copies/ml.
Indinavir = protease inhibitorAZT + 3TC = RT inhibitors
![Page 18: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/18.jpg)
Retroviruses. CSHL Press Fig. 13-18, Modified from Gulick et al. 1997
In some patients it worked exceptionally well
assay's limit of detection = 50 copies/ml
![Page 19: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/19.jpg)
Retroviruses. CSHL Press Fig. 13-18, Modified from Gulick et al. 1997
The median initial cell count was 142 cells/μl (compared to a normal value of 1000).
With viral load reduced T cellsand thus the immune system rebounded
![Page 20: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/20.jpg)
With the addition of these new drugsThe fight against AIDS in the USTook a dramatic turn for the better
![Page 21: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/21.jpg)
FDA-Approved Drugs to Treat HIV Infection
![Page 22: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/22.jpg)
Mutations associated with resistance to protease inhibitors
http://atc.atccu.chula.ac.th/biosci_PR.htm
Of course we can’t halt evolutionby natural selection
![Page 23: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/23.jpg)
Combination treatment takes time to reduce viral load
![Page 24: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/24.jpg)
Combination treatment takes time to reduce viral loadAnd it’s required for a lifetime
Why? What about the viral life cycle makes this virus so difficult to eradicate?
![Page 25: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/25.jpg)
Remember that the virus integrates into our own DNA? One infected cell can re-start the infection
Which cells in your body might harbor HIV for a long time?
![Page 26: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/26.jpg)
Picture courtesy of Frank Church
What does the future hold in terms of HIV drugs?
![Page 27: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/27.jpg)
Go back to what happens when virus enters T cells
![Page 28: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/28.jpg)
What if we could block this step?
![Page 29: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/29.jpg)
Could we target Viral fusion with host cells??
![Page 30: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/30.jpg)
A: Trimer of gp41/gp120 heterodimers
B: CD4 interaction with gp120 induces conformational change
C: Interaction with CCR5 or CXCR4 co-receptor induces gp41conformational change to insert fusion peptide into plasma membrane
D: Formation of a fusion pore through which viral core passes
HIV entry into a CD4+ T cell
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom
![Page 31: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/31.jpg)
A: Trimer of gp41/gp120 heterodimers
B: CD4 interaction with gp120 induces conformational change
C: Interaction with CCR5 or CXCR4 co-receptor induces gp41conformational change to insert fusion peptide into plasma membrane
D: Formation of a fusion pore through which viral core passes
A 36 amino acid “peptide” resembling gp41 blocks fusion
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom
![Page 32: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/32.jpg)
FDA-Approved Drugs to Treat HIV Infection
![Page 33: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/33.jpg)
Or as the drug company sees it….
![Page 34: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/34.jpg)
But guess what happens?
![Page 35: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/35.jpg)
But guess what happens?
![Page 36: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/36.jpg)
More inhibitors are in the pipeline
![Page 37: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/37.jpg)
Drug designers are also targeting integrase
Merck's Isentress (raltegravir) was approved by the FDA in October 2007.A second integrase inhibitor, Gilead's elvitegravir (GS-9137), is in advanced clinical trials.
![Page 38: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/38.jpg)
FDA-Approved Drugs to Treat HIV Infection
![Page 39: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/39.jpg)
Our understanding of the biology of HIValso has given us insights into other aspects of the disease
![Page 40: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/40.jpg)
Our understanding of the biology of HIValso has given us insights into other aspects of the disease
For example, clinicians noticed that a small fraction of people engaged in “high-risk” behaviors did not develop AIDS
![Page 41: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/41.jpg)
Our understanding of the biology of HIValso has given us insights into other aspects of the disease
For example, clinicians noticed that a small fraction of people engaged in “high-risk” behaviors did not develop AIDS
WHY NOT?
![Page 42: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/42.jpg)
Let’s do an experiment
Isolate CD4+ T cells from these people and add HIV
![Page 43: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/43.jpg)
They do not get infected!
![Page 44: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/44.jpg)
They do not get infected!
WHY NOT?
![Page 45: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/45.jpg)
Remember how the virus enters T cells?
![Page 46: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/46.jpg)
These people are mutants!
![Page 47: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/47.jpg)
Both copies of the gene encoding the co-receptor CCR5 had deletion mutations and thus they did not express a functional co-receptor
![Page 48: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/48.jpg)
Even individuals carrying one good copy of the gene and one bad copy of the gene have delayed progression from infection to AIDS
![Page 49: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/49.jpg)
Other “long-term non-progressors” generate antibodies against conserved regions of gp120 and gp41
Or have a vigorous response of killer T cells to HIV
![Page 50: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/50.jpg)
Finally, some Long-term non-progressors are infected with a mutant HIV virus lacking the accessory gene Nef
Nef function:1.Down regulate CD4 so virus can escape2.Modulates expression of other immune effector molecules
![Page 51: I guess you think you know this story. You don’t. The real one’s much more gory. The phoney one, the one you know Was cooked up years and years ago.” Roald.](https://reader037.fdocuments.in/reader037/viewer/2022103005/56649f545503460f94c789eb/html5/thumbnails/51.jpg)
Potential Therapies- Life Cycle of HIV-1
Picture courtesy of Frank Church