Re: Altri HDACi anti-latenza in fase clinica: panobinostat
Inviato: lunedì 29 aprile 2013, 11:12
Questo è un post scritto dalla virologa Abbie Smith ieri nel suo blog su ScienceBlogs. E chi vuole capire la preoccupazione che molti hanno per questo tipo di ricerche non farà fatica a coglierla:
‘Scientists on brink of HIV cure’. Ugh. UUUUUUUGH. *sigh*
*sigh*
*heaviersigh*
One of the many problems we have when treating HIV patients is that HIV can hide (latent). So a cell can be infected with HIV, but not show any signs of being infected. The HIV provirus is just chillin in the host cell DNA, not making any viral proteins/babby viruses, so the individuals immune system doesnt even have a chance to kill it.
Periodically, those ‘hidden’ proviruses will activate, and make more viruses.
Its fun to look at in a phylogenetic tree– alovasudden, a virus collected at, say, 5 years post infection, looks like the viruses that were circulating 1 year post infection. Evolutionary time-traveling, evolutionary contingency, randomly exploring alternative evolutionary pathways than what were previously randomly explored– its added fun to the HIV-1 quasispecies.
… And an added complication to curing HIV infection.
So a lot of scientists have done a lot of work trying to figure out how to stop latency. Dont let HIV hide/time-travel.
The problem is (that is, of the many problems, this is one example), latency is not simple. Its not ‘BLOCK X = Activation!’ ‘ADD Y = Activation!”
So what some folks are trying is an epigenetic modifying drug (weird! theyre using pharmaceuticals, not religion or positive thinking to modify patients epigenetics! its as if epigenetics is just biochemistry and NOT MAGIC).
Even though there are *many* layers of epigenetic control of HIV, they are hoping that this one drug that does this one thing will knock all latent HIVs out of their slumber and then, I dunno, CTLs or something are supposed to kill the infected cells, and HIV CURED!
I welcome another weapon in our anti-HIV arsenal.
I do not welcome this:
That is so unhelpful, Mr. Simons.
My Debbie Downer take:
1– Does the drug get to where it needs to be? Apparently Panobinostat can cross the blood-brain-barrier, which was my first concern. Lots of HIV hiding in immune cells in the brain. If the drug cant get there, it cant work.
2– Does the drug active all of the infected cells? All of them. ALL OF THEM. Because with HIV, 85%, 95%, 99% dont cut it. Go ask AZT how ‘Well, it stops most of the viruses?’ worked out for it. To quote Dr. Ian Malcolm, ‘Life… uh… finds a way.’
3– What else does this drug do? Epigenetic modifiers are no joke. Screwing around with epigenetics is a great way to get cancer (and who knows what else). HDAC inhibitors are not ‘only’ going to screw with HIV proviruses. So what are the side effects of this drug? Are we going to cure their HIV, activate an ERV, and give them MS?
4– Most importantly, for me as a virologist: Activated HIV proviruses mean lots and lots and lots of babby viruses… Lots of babby viruses that all look and behave slightly different from all the other babby viruses, aka, a quasispecies. The patients immune system cant neutralize all of them immediately. I mean, that is the reason (again, one of the reasons out of many) why you never get better. Red Queen. Your adaptive immune system is reactive. By the time it reacts to the virus, its gone. Its changed. So your immune system has to adapt again.
What if you give patients these drugs, and all you do is turn 1000 infected cells into 100000000000000000000000000000 infected cells? What if all this treatment does is *rapidly* accelerate disease progression?
I hope it works. I hope its a cure. But if its not, I hope it does nothing.
‘Scientists on brink of HIV cure’. Ugh. UUUUUUUGH. *sigh*
*sigh*
*heaviersigh*
One of the many problems we have when treating HIV patients is that HIV can hide (latent). So a cell can be infected with HIV, but not show any signs of being infected. The HIV provirus is just chillin in the host cell DNA, not making any viral proteins/babby viruses, so the individuals immune system doesnt even have a chance to kill it.
Periodically, those ‘hidden’ proviruses will activate, and make more viruses.
Its fun to look at in a phylogenetic tree– alovasudden, a virus collected at, say, 5 years post infection, looks like the viruses that were circulating 1 year post infection. Evolutionary time-traveling, evolutionary contingency, randomly exploring alternative evolutionary pathways than what were previously randomly explored– its added fun to the HIV-1 quasispecies.
… And an added complication to curing HIV infection.
So a lot of scientists have done a lot of work trying to figure out how to stop latency. Dont let HIV hide/time-travel.
The problem is (that is, of the many problems, this is one example), latency is not simple. Its not ‘BLOCK X = Activation!’ ‘ADD Y = Activation!”
So what some folks are trying is an epigenetic modifying drug (weird! theyre using pharmaceuticals, not religion or positive thinking to modify patients epigenetics! its as if epigenetics is just biochemistry and NOT MAGIC).
Even though there are *many* layers of epigenetic control of HIV, they are hoping that this one drug that does this one thing will knock all latent HIVs out of their slumber and then, I dunno, CTLs or something are supposed to kill the infected cells, and HIV CURED!
I welcome another weapon in our anti-HIV arsenal.
I do not welcome this:
That is so unhelpful, Mr. Simons.
My Debbie Downer take:
1– Does the drug get to where it needs to be? Apparently Panobinostat can cross the blood-brain-barrier, which was my first concern. Lots of HIV hiding in immune cells in the brain. If the drug cant get there, it cant work.
2– Does the drug active all of the infected cells? All of them. ALL OF THEM. Because with HIV, 85%, 95%, 99% dont cut it. Go ask AZT how ‘Well, it stops most of the viruses?’ worked out for it. To quote Dr. Ian Malcolm, ‘Life… uh… finds a way.’
3– What else does this drug do? Epigenetic modifiers are no joke. Screwing around with epigenetics is a great way to get cancer (and who knows what else). HDAC inhibitors are not ‘only’ going to screw with HIV proviruses. So what are the side effects of this drug? Are we going to cure their HIV, activate an ERV, and give them MS?
4– Most importantly, for me as a virologist: Activated HIV proviruses mean lots and lots and lots of babby viruses… Lots of babby viruses that all look and behave slightly different from all the other babby viruses, aka, a quasispecies. The patients immune system cant neutralize all of them immediately. I mean, that is the reason (again, one of the reasons out of many) why you never get better. Red Queen. Your adaptive immune system is reactive. By the time it reacts to the virus, its gone. Its changed. So your immune system has to adapt again.
What if you give patients these drugs, and all you do is turn 1000 infected cells into 100000000000000000000000000000 infected cells? What if all this treatment does is *rapidly* accelerate disease progression?
I hope it works. I hope its a cure. But if its not, I hope it does nothing.