treatment intensification=worthless for your brain

[wtfimpoz]

http://www.aidsmeds.com/rssredir/articles/hiv_reservoir_brain_1667_19506.shtml

At least for to me, this "discovery" seems to create more questions than it answers.  If anyone has any explanations, I'd be greatful for their input.

1)  For starters, I thought it was settled that blood/brain barrier penetration with current ARVs provided nominal to zero protection against the virus' impact on the brain, as demonstrated through cognitive outcomes in persons on different regimes with undetectable viral loads.  I have always been confused by the current trend in favor of greater BBB penetration.  Why did we think that therapy with existing ARVs would be effective to begin with?  Were all of these smart people really getting hung up on that study on AZT monotherapy?

2)  I also thought it was settled that treatment intensification as a whole did nothing to affect the contents of viral resevoirs.  Why did we think that this would be different in the brain?

3)  When we talk about measuring resevoirs, either in the blood or in the brain, how do we do that?

4)  "First, the data indicate that the tiny bit of detectable HIV in the brain is not due to active reproduction"
When we refer to the brain, are we referring to actual brain tissue, or to CSF?  I've seen the two phrases used interchangeably, though to be certain HIV can directly infect the brain.  It seems illogical to conclude that simply because we found viral presence in the brain after treatment intensification it is true that the virus is not actively replicating in this resevoir.  Do we know or have good reason to believe that infected brain cells respond to antiretrovirals in the same way that cd4 cells do?  For the life of me, I have not found anything which discusses the direct infection of brain tissue by HIV.

5)  If HIV is NOT actively replicating in the brain resevoirs, why is it that it oftentimes takes years or even decades for the virus to impact cognitive performance?  Is it common for other types of brain damage to take YEARS to manifest?

6)  Can anyone concisely explain what "inflammation" is, specifically in this context?  I've searched The Lessons and the internet as a whole.  From the context it appears to be a constellation of symptoms which look a lot like premature aging.  Is this correct?

7)  I know that the liklihood of someone experiencing cognitive issues is loosely correllated with a host of factors, including the duration between infection and treatment, nadir cd4, history of treatment interruption, and discordancy between blood and CSF.  All of these correllations are poor.  Operating off the theory that the brain is a resevoir, and not a site of active replication, has anyone explored the liklihood that not everyone who is infected with HIV has had the virus progress to their brain, and that in some people the virus may progress to the brain at different rates?  A few positive cadavers and a tissue sample should answer this question.  Since the first three serve as proxies for the degree to which the virus "runs rampant" without medication, might we infer that the virus continues to establish resevoirs in the brain long after seroconversion.  If this is so, and if the virus is not actually replicating in the brain, shouldn't the public health implication be to begin treatment immediately?  (I realize I'm "drawing a long bow" as Matty would say, but it follows in my mind)

8 )  Don't most people with undetectable blood VL have undetectable VL in their CSF?

9)  "If there is no active replication, and infected cells are simply releasing intact virus, then the only way to get rid of it will be to purge these infected cells entirely"  With all respect to the author, this seems a false dichotomy.  Wasn't there recently an israeli discovery where they discovered a way to destroy HIV which was resting within cells without harming the infected cell?  Couldn't we compel the HIV to enter a phase of perpetual dormancy within the infected cells?  The image this quote renders is of neurosurgeons literally scraping the brains of pozzies.

10)  In regards to the question of whether the brain is a site of active replication or not, I know that the Berlin Patient has an undetectable CSF.  Did we measure his CSF beforehand?

11)  Does the liklihood of viral discordancy between blood and CSF increase with the estimate period of time one is infected?

12)  Does Interleukin penetrate the blood brain barrier?

..and so much more.  If anyone responds, thanks in advance.

EDIT:  My prediction for the interleukin trials:  No one is cured, we get another expensive treatment designed to improve our quality of life.  Anyone wanna take bets?

[MitchMiller]

I don't have a link, but there was a study done a couple years ago or so, that documented  strains of the virus in the brains of HIV+ cadavers that were unique to the rest of the body.  The implication was that the virus is replicating in the brain, compartmentalized from the virus/meds in the rest of the body.

There is a cancer med that kills HIV infected cells in the lab  (perifosine that is a in a class of drugs with a property to seek out and destroy HIV infected cells).  It does cross the blood brain barrier.  Check out figure 5 in the article.  http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2948033/#pone.0013121.s001 

Looks pretty potent when combined with SNP.  I'm wondering if/when the company will license it out to anyone for clinical trials, since they are focused only on cancer.