Transcript HIV Treatment II

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 Dahl
“Revolting Rhymes”
Reverse transcriptase inhibitors were a
Major breakthrough in treating AIDS
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
http://www.avert.org/his81_86.htm
And AZT and other RT inhibitors started to level off
the rise in AIDS cases
http://www.avert.org/his81_86.htm
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 treatment
teach us about how we might approach things?
We need a new drug target
Enzymes make good drug targets
what other enzymes does HIV use?
Let’s look here!
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
You want a drug that fits into the “active site”
Where the enzyme does its work
Das, Amit et al. (2006) Proc. Natl. Acad. Sci. USA 103, 18464-18469
Copyright ©2006 by the National Academy of Sciences
You start with its natural substrate:
a polypeptide backbone and
the site of protease cleavage (arrow)
Retroviruses. CSHL Press Fig. 13-15
You look for things with a similar shape
In part of the molecule
Retroviruses. CSHL Press Fig. 13-15
These can fit into the “active site” and stop up the works
preventing the enzyme from doing its work
www.clubbiotech.at/ blundell.htm
The “protease inhibitors”
that pass further tests become drugs!
December 1995
The 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?
December 1995
The 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.
Combination therapy worked well
The baseline median viral RNA level in this study was 41,000 copies/ml.
Indinavir = protease inhibitor
AZT + 3TC = RT inhibitors
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
Retroviruses. CSHL Press Fig. 13-18, Modified from Gulick et al. 1997
With viral load reduced T cells
and thus the immune system rebounded
The median initial cell count was 142 cells/μl (compared to a normal value of 1000).
Retroviruses. CSHL Press Fig. 13-18, Modified from Gulick et al. 1997
With the addition of these new drugs
The fight against AIDS in the US
Took a dramatic turn for the better
FDA-Approved Drugs to Treat HIV Infection
Of course we can’t halt evolution
by natural selection
Mutations associated with resistance to protease inhibitors
http://atc.atccu.chula.ac.th/biosci_PR.htm
Combination treatment takes time to reduce viral load
Combination treatment takes time to reduce viral load
And it’s required for a lifetime
Why? What about the viral life cycle makes this virus
so difficult to eradicate?
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?
What does the future hold in terms of HIV drugs?
Picture courtesy of Frank Church
Go back to what happens when virus enters T cells
What if we could block this step?
Could we target Viral fusion with host cells??
HIV entry into a CD4+ T cell
A: Trimer of gp41/gp120 heterodimers
B: CD4 interaction with gp120 induces conformational change
C: Interaction with CCR5 or CXCR4 co-receptor induces gp41
conformational change to insert fusion peptide into plasma membrane
D: Formation of a fusion pore through which viral core passes
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom
A 36 amino acid “peptide” resembling gp41 blocks fusion
A: Trimer of gp41/gp120 heterodimers
B: CD4 interaction with gp120 induces conformational change
C: Interaction with CCR5 or CXCR4 co-receptor induces gp41
conformational change to insert fusion peptide into plasma membrane
D: Formation of a fusion pore through which viral core passes
THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and Swanstrom
FDA-Approved Drugs to Treat HIV Infection
Or as the drug company sees it….
But guess what happens?
But guess what happens?
More inhibitors are in the pipeline
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.
FDA-Approved Drugs to Treat HIV Infection
Our understanding of the biology of HIV
also has given us insights into
other aspects of the disease
Our understanding of the biology of HIV
also 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
Our understanding of the biology of HIV
also 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?
Let’s do an experiment
Isolate CD4+ T cells from these people and add HIV
They do not get infected!
They do not get infected!
WHY NOT?
Remember how the virus enters T cells?
These people are mutants!
Both copies of the gene encoding the co-receptor
CCR5 had deletion mutations and thus they did not
express a functional co-receptor
Even individuals carrying one good copy of the gene
and one bad copy of the gene have delayed
progression from infection to AIDS
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
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 escape
2. Modulates expression of other immune effector molecules
Potential Therapies- Life Cycle of HIV-1
Picture courtesy of Frank Church