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.
You are right about epigenetic modifiers being rather dirty drugs - the only exception I've seen to that trend is where they dropped the doses of decitabine (a demethylating agent) right down and were able to see effects on cancer cells but not on normal stem cells (admittedly they only had normal haematopoietic controls).
I think the best way a cure will be alighted upon will be to isolate non-CD4 haematopoietic stem cell precursor and use TALENs or CRISPR to engineer the CCR5 delta 32/delta 32 genotype into them (or conversely, wreck the receptor by targeting the start codon/first exon) and then put them back in to reconstitute the immune system.
Now, if you figure out how to activate it, doesn't that mean you have identified a receptor? So it should be possible to to block the receptor without activating it, permanently inactivating (at least via this mechanism) the latent virus.
As usual a very enlightening article. Good work and thanks!
What #1 supposed to read as "Apparently Panobinostat can *NOT* cross the blood-brain-barrier, which was my first concern."?
Correct to my own comment:
@AbbieSmith -- Apologies for the off-topic question, but I can't figure out how to post or send something directly to you.
Today's ScienceNews has a report of a "paleovirology" analysis of HepB fragments in the zebra finch genome (http://www.sciencenews.org/view/generic/id/350053/description/Genetic_f…). Is this sufficiently interesting that you might consider explaining the details, without journalistic spin, to the rest of us?
CONGRATULATIONS ON YOUR PUBLISHED PAPER!!!~ 111
I do not welcome this:
Scientists on brink of HIV cure
That is so unhelpful, Mr. Simons.
It could be worse.
Warning, link goes to pop-ups, autoplay ads and brain damaging levels of dumb.
(Also, why is sci-blogs speaking to me in German?)
They've actually edited the article today, including removing the suggestion that people in the panobinostat trial might be cured and changing the quotes to add caveats about the fact that HDAC inhibitors may only cause a small proportion of latently infected cells to express HIV proteins (as discussed in this excellent Nature Medicine news article: http://www.nature.com/nm/journal/v19/n4/full/nm0413-384.html).
But it's closing the proverbial barn door given how many other outlets--including UPI etc.--have picked up and trumpeted the original piece. They also didn't change the title.
Hey Abbie nice dissection of the Cure news that's been floating around.
I really like your poke at the evolutionary red queen theory.
"A slow sort of country!" said the Queen. "Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!" (from wiki)
So perhaps we need to supercharge our immune system.
To run twice as fast and perhaps 3x as fast?
And what happens when we slow the race down? Using ARVs and immunotoxins (http://pag.ias2013.org/Abstracts.aspx?AID=1883?)
Will the immune system then have a fighting chance against the impending war of awakening the sleeping soldiers? :P
Perhaps with the bringing in of ecological and evolutionary concepts, removing the "food" source of HIV ie CD4 receptors as with what companies like calimmune and sangamo are trying out maybe viable combination dont you think?