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Author Topic: Flushing out latent infection  (Read 18845 times)

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Offline J220

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Flushing out latent infection
« on: June 28, 2006, 07:51:10 PM »
Not sure if you have seen this before, but here is an interesting article on research designed to flush out and clear latent infection (i.e. cure). The original link (credit goes to the tireless golddrake!) is http://www.gladstone.ucsf.edu/gladstone/site/annualreport/section.php?id=1451 .

Understanding HIV Latency at the Molecular Level

Eric Verdin

www.gladstone.ucsf.edu/givi/verdin

Treatment with highly active antiretroviral therapy can control HIV infection for prolonged periods. Viral loads are suppressed to undetectable levels, and patients show marked clinical and biological improvement. However, owing to the persistence of a pool of cells harboring a latent form of HIV, the virus reemerges rapidly once therapy is interrupted. These cells contain a transcriptionally inactive integrated HIV genome.

Our laboratory is interested in understanding the molecular mechanism responsible for the establishment, maintenance, and reactivation of latent HIV.
In several studies during the past year, we made significant progress in understanding HIV latency and the mechanism leading to the reactivation of latent HIV. For example, we recently developed the first laboratory model of HIV latency.
     
In collaboration with Rick Bushman (University of Pennsylvania), we analyzed the site of integration of latent HIV. This analysis confirmed that latent HIV preferentially integrates in heterochromatin and in gene deserts, consistent with the fact that these genome domains are not conducive to transcription. However, we also found many latent sites within actively transcribed genes, an unexplained observation.

Recently, we demonstrated that the human chromatin remodeling complex SWI/SNF is critical for the activation of the HIV promoter during latency reactivation. Human SWI/SNF interacts with Tat and is recruited to the HIV promoter, where it remodels a single nucleosome at the transcriptional start site. Four of our latent cell lines contained an HIV genome integrated into the first intron of the Brd4 gene. Brd4 protein is a component of the pTEFb complex, which plays a critical role in HIV transcription. We are now testing the role of Brd4 in Tat-mediated transcriptional activation of the HIV promoter and in latency.

In other studies, we collaborated with Warner Greene's group to study the role of NF-κB in the establishment of HIV latency.

Finally, using our latent cell lines, we identified six drugs (of 16,000 tested) that reactivate latent HIV. Such drugs could be used in patients to flush out their latently infected cells and eliminate latent pools (flushing hypothesis). If successful, this strategy could form the basis for a therapy to eradicate HIV infection in patients.




Latent and productive HIV infection. A productive HIV infection is associated with viral production and leads to cell death, while latently infected cells do not produce virus and can persist. Activation of latently infected cells leads to reactivation of the virus and is a potential therapeutic approach to deplete the latent reservoir.

Recent Publications

Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C, Hannenhalli S, Verdin E, Berry CC, Ecker JR, Bushman FD (2005) Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J. Virol. 79:6610–6619.

Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC (2006) NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25:139–149.
« Last Edit: June 28, 2006, 07:54:04 PM by J220 »
"Hope is my philosophy
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Offline J220

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Re: Flushing out latent infection
« Reply #1 on: June 28, 2006, 08:05:25 PM »
So, a separate comment on this...if in fact any of the six drugs identified can and does work at activating latent infected cells, then what we could see in the future is a therapy regime, say of a month or two, where the patient takes the "activating"or flushing drugs while taking anti-retrivirals (whichever they decide work best in conjunction with this) at the same time. So you have two actions, waking up the latent cells, and when they become productively infected cells then the anti-viral medicine kills it off in the blood stream. Once there is no more latent infection, or any active cells in the blood, then a patient is cured!

Could it turn out to be that simple?????????????????

« Last Edit: June 28, 2006, 08:10:48 PM by J220 »
"Hope is my philosophy
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Love of Life means hope for me
Born on a New Day" - John David

Offline HIVworker

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Re: Flushing out latent infection
« Reply #2 on: June 28, 2006, 09:42:11 PM »
So, a separate comment on this...if in fact any of the six drugs identified can and does work at activating latent infected cells, then what we could see in the future is a therapy regime, say of a month or two, where the patient takes the "activating"or flushing drugs while taking anti-retrivirals (whichever they decide work best in conjunction with this) at the same time. So you have two actions, waking up the latent cells, and when they become productively infected cells then the anti-viral medicine kills it off in the blood stream. Once there is no more latent infection, or any active cells in the blood, then a patient is cured!

Could it turn out to be that simple?????????????????



That's the idea, yes. If it turns out to be that simple. There are a couple of concerns but that is the general strategy.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline J220

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"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline Jake72

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Re: Flushing out latent infection
« Reply #4 on: June 29, 2006, 01:49:02 PM »
Is this anywhere beyond the test tube stage?

Offline HIVworker

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Re: Flushing out latent infection
« Reply #5 on: June 29, 2006, 01:57:44 PM »
No it isn't. I know one of the authors, it was her PhD project.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline blondbeauty

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Re: Flushing out latent infection
« Reply #6 on: June 29, 2006, 02:08:03 PM »
And if we squeeze every single cell?
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Offline J220

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Re: Flushing out latent infection
« Reply #7 on: June 29, 2006, 02:19:19 PM »
I just sent an email to Dr. Verdin, let's see if he wants to talk about any plans to start a clinical tril going. Will keep you posted.
"Hope is my philosophy
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Love of Life means hope for me
Born on a New Day" - John David

Offline J220

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Re: Flushing out latent infection
« Reply #8 on: June 29, 2006, 02:26:51 PM »
That's the idea, yes. If it turns out to be that simple. There are a couple of concerns but that is the general strategy.

R

I guess one of the concerns would be of waking up all the latent cells at the same time and having uncontrolled viral replication....but wouldn't medications taken concurrently prevent this from happening?
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline Jake72

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Re: Flushing out latent infection
« Reply #9 on: June 29, 2006, 06:23:09 PM »
yeah, wouldn't the latent cells be awakened and immediately zapped by the medications?  (I'm imagining a sort of pharmaceutical equivalent of one of those porch bug zappers)

Offline J220

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Re: Flushing out latent infection
« Reply #10 on: June 29, 2006, 07:24:42 PM »
I'm sure it would work that way, but I would guess they are going to be very cautious on trying this, initially. The last thing they would want is to have a patient get worse. I know that the valproic acid approach had a way of preventing that happening, I think the latent cells were unmasked in a way that wouldn't cause replication. Maybe these drugs work on the same principle. I do know this, if they find a way of turning all latent cells to productive cells this would be a major breakthrough. Maybe we are closer to a cure than we think...
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline whizzer

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Re: Flushing out latent infection
« Reply #11 on: June 29, 2006, 07:33:30 PM »
It sounds intriguing.

Unfortunately, even at undetectable levels, some viral replication is still taking place, and new CD4s are being created and going into a resting state all the time.  Even if you wake them all up at once, new CD4s being produced and going to rest could possibly be infected, thus maintaining a reservoir of virus.

So first it must be determined if you can keep newly created CD4s from becoming infected prior to entering the resting state.  That is, can we lower the number of infected cells in the latent reservoir with our current medications?  Alas, this has yet to be determined.  There is a study looking into this now, and it is still recruiting, but you must be treatment naive to participate.  I am currently enrolled in this study.

If, in fact, we can prevent cells from becoming infected, then it seems reasonable that if you could speed up the pace at which cells come out of the resting state, then it may be possible to clear the virus.  The half-life of a resting CD4 is 44 months.  If you can prevent infection of uninfected CD4s with entry inhibitors, it is hypothesized that you could eventually clear the virus, but it would take a long course of therapy.  Decrease the half life of a resting cell, and you would increase the rate of clearance, assuming you can maintain suppression of viral replication during this period.

Even with all the unknowns and unanswered questions, discoveries like this give me hope.

Offline HIVworker

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Re: Flushing out latent infection
« Reply #12 on: June 29, 2006, 07:49:47 PM »
Whizzer is sort of right here.

Latent infection is one thing, persistant infection is another. Imagine that HIV replication is like a fire and the fuel is CD4 cells. The smoke is the viral load. As HIV burns through CD4 cells, the viral load goes up (smoke increases). When HAART is present, the fire goes down and the viral load (smoke) decreases. However, if you use a very sensitive PCR test you can find the remains of the fire still smouldering. It's not out. In my opinion the current viral load test doesn't take into account where this other fire is burning. Only when you find where it is will you decrease the rate of depletion of CD4 cells (which the body does) and you will decrease the chance that resistance will occur. Current drugs don't touch this place or if they do they only partially do. The next big thing in the HIV world will be to find this place. Once you know where it is, you can destroy it.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline J220

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Re: Flushing out latent infection
« Reply #13 on: June 29, 2006, 08:15:33 PM »
The subject of reservoirs is more than a little controversial. For example it is not know if in fact there is a large, collective reservoir, with a half life of years, or as you mention, this is a function of ongoing low level replication that contunually deposits, as it were, infected cells into the so-called reservoir.

Having said that, I see it this way. If these drugs can in fact unmask, or activate latent cells to become productive cells efficiently, then even if newly-created CD4 cells are infected and become latently-infected cell, then these cells themselves will become productive after exposure to the drugs, then killed off by art, and the cycle will start again, but hopefully with a negative trend, with less and less new cels entering a latent state until some kind of asymptote is reached (how about zero) and the damn thing is gone forever.

By the way I just received a reply from Dr. Verdin. He states that they are planning to test their 'flushing out'  hypothesis first in chimpanzees infected with SIV, likely in 2007. Based on these results, a decision will be made  to pursue the same approach in humans. He did suggest that I contact D. Margolis, who is also working on the latency issue.

If I get more emails I'll pass them on here.
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline HIVworker

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Re: Flushing out latent infection
« Reply #14 on: June 29, 2006, 08:55:50 PM »
Just a side note. I am not sure that cells infected with HIV are killed by ART. They are targets for the host immune system and it is this that clears them.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline blondbeauty

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Re: Flushing out latent infection
« Reply #15 on: June 29, 2006, 09:15:05 PM »
And if the place in which the virus hides is the brain...we should destroy it?
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
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Offline HIVworker

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Re: Flushing out latent infection
« Reply #16 on: June 29, 2006, 09:32:54 PM »
You mean in neurons?
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline J220

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Re: Flushing out latent infection
« Reply #17 on: June 29, 2006, 11:44:22 PM »
I am reaching the limit of my scientific know-how here, but if drug is found to turn latent cells into productive ones, wouldn't it be more or less irrelevant where the latent cells are? Once the drug is taken isn't it diffused throught the system, even in the brain?
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline whizzer

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Re: Flushing out latent infection
« Reply #18 on: June 29, 2006, 11:56:24 PM »
My clinical study is in Chapel Hill.  I've heard David Margolis is working on a few things with regards to attempting to clear the virus, but have not heard any details.  I'm hoping he'll be doing a larger Valproic Acid study that I can get in as a follow on to the one I'm in now, but I've not heard anything about that.  I've heard the term 'blood washing' mentioned, but I have NO idea what that entails.

Offline HIVworker

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Re: Flushing out latent infection
« Reply #19 on: June 29, 2006, 11:59:05 PM »
J220

Drugs do not just wash all over the body when they are taken...specifically the brain. The brain is a nightmare for drug discovery due to what is called the blood-brain-barrier (BBB). This actively kicks out things and stops many drugs getting into the brain. There are some NNRTIs and NRTIs that cross the BBB but to what extent we don't actually know. We do know that many drugs in HAART don't cross the BBB. Some that do give you funky dreams, although I am not sure if there is a direct correlation for all.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline J220

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Re: Flushing out latent infection
« Reply #20 on: July 01, 2006, 12:34:34 AM »
Whizzer, what is the clinical trial you are participating in?
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline blondbeauty

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Re: Flushing out latent infection
« Reply #21 on: July 01, 2006, 06:52:17 AM »
Yes I meant Neurons. I don´t use them too much but would like to preserve them.
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
Last CD4 count (OCT 2013): 52%= 933

Offline Jake72

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Re: Flushing out latent infection
« Reply #22 on: July 01, 2006, 10:36:32 AM »
I'm aware of the blood/brain barrier, but I would think that this obstacle could, in theory, be overcome.  Look at syphilis (yes, I know, a bacterial infection), which eventually enters the brain and cause madness.  60 years (!) ago, scientists discovered that antibiotics could cure syphilis (even at later stages, supposedly) , so I'm assuming that this meant that they could penetrate the blood/brain barrier and do their work.

Offline lydgate

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Re: Flushing out latent infection
« Reply #23 on: July 01, 2006, 07:24:02 PM »
I read the reports about the valproic acid study last year; thought of it as good news, dismissed the hype about a "cure," and then thought no more of it. Until today.

I started Depakote (500 mg bid) a few days ago as an adjunct therapy, for its mood-stabilizing properties. (I do not have epilepsy nor am I bipolar 1 or 2, just plain old depression -- puzzlingly recurrent with very brief "mini-episodes" over the last year.). In the Margolis study, all four patients were on HAART, which was intensified with the addition of T-20 to prevent (or curb) increased viremia.

I'm not on any medications. My lab numbers are (as of March, the six-month point after seroconversion): CD4 757, CD4% 38, VL 70 copies. Too early to talk of a low virologic set point, but I was/am cautiously optimistic. I go in for my next labs on July 19. With the addition of valproic acid, though, I'm puzzled, intrigued, and mildly worried.

My questions are:

1. Do HIV-positive individuals NOT on HAART even have latent reservoirs or "resting, infected" T-cells?

2. Assuming that the answer to 1. is "Yes" then it's entirely possible/likely that the valproic acid in my body, through its inhibition of HDAC1, will cause a decline in my "resting, infected" cells. Does that mean that my CD4 count, using conventional tests, will also decline?

3. The Margolis study seems to have used an ultra-ultrasensitive assay, and viral loads in all four patients remained below 1 copy for most of the study. Is this because of the intensified HAART (triple cocktail plus T-20) or some other reason? I'm not on HAART; valproic acid was predicted to stimulate the release of HIV particles from resting, infected cells. In the absence of HAART to curb my viremia, can I expect my viral load to go up?

4. Is there any work being done with the thousands of HIV-positive individuals -- on HAART or not -- taking valproic acid for psychological reasons, and how this affects their immune system and viremia?

Apologies if these questions sound naive, I'm not a scientist. Any answers, even speculative ones, appreciated.

Jay
Her finely-touched spirit had still its fine issues, though they were not widely visible. Her full nature, like that river of which Cyrus broke the strength, spent itself in channels which had no great name on the earth. But the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.

George Eliot, Middlemarch, final paragraph

Offline dario

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Re: Flushing out latent infection
« Reply #24 on: July 01, 2006, 08:39:16 PM »
Jay,

This article can help:  http://ww2.aegis.com/pubs/jhopkins/2005/JH2005-09-05.html

The problem with flushing out reservoirs of hiv are basically two:
1. reactivation of latent cells has to be 99.9999%
2. there may be other places this unknown where this bug hides.

From what I've read the best effect of this valproic acid is that it enters the brain and therefore it could be useful to alleviate symptoms oft hiv-related dementia.

ciao

... when I was young, I never needed anyone, making love was just for fun, those days are gone ... Eric Carmen (Raspberries)

Offline J220

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Re: Flushing out latent infection
« Reply #25 on: July 01, 2006, 09:47:39 PM »
Hey lydgate, I am not a scientist either so keep this in mind with my response.

I believe that the method by which valproic acid unmasks resting infected cells does not allow the cells to become productive cells (as in viral-replicating). The addition of the T-20 in the proof-of-concept study was just a safeguard, I believe.

The question of the experience of those who have been using VPA for a long period of time is a good one, and I remember reading somewhere (it may be in one of the links in this thread) that researchers were gathering data like that, to help see the possiblity if using vpa as a treatment, or a cure.

Since you are taking VPA now I would suggest that you contact margolis' research team, they may be able to answer your questions or may even be interested in keeping on touch with you, to track your experience.

About reservoirs in general, there is much that is not known, and you will always see researchers saying that there may be more than one reservoir, but conversely no one really knows if there is more that one, or even if there is such a thing as a reservoir, to begin with.

In any case, HIV worker may be able to shed some more knowledgeable light on your questions. Do keep us all posted though, regarding your experience with VPA! J.
« Last Edit: July 01, 2006, 09:50:25 PM by J220 »
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline HIVworker

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Re: Flushing out latent infection
« Reply #26 on: July 01, 2006, 10:13:40 PM »
First off, HIV and neurons. Currently I have not come across any research that strongly suggests that HIV can infact infect neurons. HIV replication in the brain is documented, but not from neurons. If it did infect the brain and produce virions, the dementia involved in HIV would be much more severe.

Valproic acid is an inhibitor of a protein called HDAC, which stands for histone deacetylase. Research has shown that HIV integration into tightly packed areas of DNA leads to no transcription (expression) from this site. The tightness of the packing is controlled by histones and HDAC keeps it this way. HDAC is one of the genes involved in keeping it silent. If you remove the clamp, HIV replication starts and the cell either dies or is killed. Adding Valproic acid will hopefully remove some of the latent infection.

Knowing this, you ask whether valproic acid will decrease your T-cell count. My answer would be yes, but not enough that it will be quantifiable. This is because the number of resting T-cells that harbor latent infection is a very low number (quantified as less than 1%). You don't want these cells anyhow, as they are merely dormant HIV factories. When they become activated, they will activate HIV-expression. So losing them is not going to hurt you. Everyone's T-cell counts contain some latent cells.

The latent pool is established in acute infection and is thought to be refilled during chronic infection.

I can't answer your 4th question, but I would imagine that the answer is yes.

On a final note, NEVER apologise for asking questions. Your questions are astute and thoughtfull. I encourage you to continue to think about it, as it helps me think about it too.

Best,

R.

PS. I'll post something about reservoirs later. It's not an easy topic to condense.
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline HIVworker

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Re: Flushing out latent infection
« Reply #27 on: July 01, 2006, 10:18:12 PM »
On another note, I don't think you need to kill 100% of latent cells. Just the vast majority would do. If you got rid of HIV replication elsewhere, the immune system would recover and be armed with the anti-HIV tools to clear another infection. It would essentially take HIV back to the time it first infected the body only this time with an immune system with tools to clear it. I predict the body would win that war.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline lydgate

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Re: Flushing out latent infection
« Reply #28 on: July 01, 2006, 10:51:59 PM »
Well, the part that continues to worry me a little is (and now I'm quoting from the Silicianos' skeptical report): "The underlying assumption of the study was that activation of latent HIV in a patient on HAART would lead to death of the infected cells without further spread of the virus."

The point being, of course, that I'm not on HAART. If, in fact, the HDAC inhibition leads to a flushing out of some 75% of the latently infected cells, then the logical conclusion would be that viremia would increase, but that an intensive HAART regimen would take care of that increase. (is that logic sound?)

My specialist told me that the early indications were that I either have (i) a good immune response to the virus or that (ii) I contracted a wimpy strain of the virus or (iii) both. Time will tell I suppose. So, I'll wait for more blood work and see what's going on; perhaps my body's defenses are good enough against the hypothetical increased viremia (in the absence of HAART). I'm certainly not going on meds with CD4s in the mid-700s and a barely detectable VL.

Perhaps I should contact the Margolis team. I can look it up on the UNC site but I believe that whizzer is at Chapel Hill too and maybe he can pass on the details (and comment on the wisdom of randomly contacting researchers).

"Blood washing" -- I doubt whether that's analagous to the "semen wasing" techniques used with serodiscordant couples who want children.

Btw, HIVworker, it seems that Robert Siliciano would disagree with you on the "vast majority" of latent cells needing to be killed. In the Aegis-Hopkins report (see link posted by dario), the authors contend that 99.9999% 0f resting, infected cells would need to be killed. Expanded comments on why you disagree with that?

Jay
« Last Edit: July 01, 2006, 11:00:20 PM by lydgate »
Her finely-touched spirit had still its fine issues, though they were not widely visible. Her full nature, like that river of which Cyrus broke the strength, spent itself in channels which had no great name on the earth. But the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.

George Eliot, Middlemarch, final paragraph

Offline HIVworker

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Re: Flushing out latent infection
« Reply #29 on: July 01, 2006, 11:27:04 PM »
It's a semantic thing. I just said you don't have to kill all of them (100%) but the vast majority would do. Its similar to how you cure cancer. You don't need to kill all cells, just the overwhelming majority of them. You want me to put a number on that - no idea. Above 99%. 99.999999%. Sure, why not. I don't think he knows either.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline lydgate

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Re: Flushing out latent infection
« Reply #30 on: July 02, 2006, 12:03:13 AM »
Couple of links I found using a simple Google search:

http://www.theannals.com/cgi/content/abstract/33/10/1113

http://www.cpa-apc.org/Publications/Archives/CJP/2001/May/Effect.asp

Time to get my psych people and my ID people talking, I think.
Her finely-touched spirit had still its fine issues, though they were not widely visible. Her full nature, like that river of which Cyrus broke the strength, spent itself in channels which had no great name on the earth. But the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.

George Eliot, Middlemarch, final paragraph

Offline J220

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Re: Flushing out latent infection
« Reply #31 on: July 02, 2006, 12:57:56 AM »
The fact is no one knows for sure the true mechanism of what is referred to as a reservoir. Even if Gallo says that 100% of the resting infection needs to be cleared, it's still a speculative statement. And since we do not have, as of yet, a treatment that is 100% effective in blocking active replication, we really cannot say what will happen to the infection as a whole then. If the anti-tat or ribozyme therapies currently being tested work to block all replication, who knows, maybe that's will do the trick.
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline J220

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Re: Flushing out latent infection
« Reply #32 on: July 02, 2006, 01:05:21 AM »
Hey lydgate, in my experience reserchers in general will take the time to respond to direct emails. so if I were you I would not hesitate to write to anyone of Margilis' team, or even him directly, with your inquiry and concerns. Go for it.
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline dario

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Re: Flushing out latent infection
« Reply #33 on: July 02, 2006, 08:06:40 AM »
J220,
what are the ribozyme therapies?
... when I was young, I never needed anyone, making love was just for fun, those days are gone ... Eric Carmen (Raspberries)

Offline dario

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Re: Flushing out latent infection
« Reply #34 on: July 02, 2006, 08:22:34 AM »
J220,
I meant to ask why do you think that this gene therapy would be effective.  (I've read that it is based on stem-cell non-embryonic genetic engineering and that a 41 year old chap from California is doing well with this treatment).
... when I was young, I never needed anyone, making love was just for fun, those days are gone ... Eric Carmen (Raspberries)

Offline J220

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Re: Flushing out latent infection
« Reply #35 on: July 02, 2006, 12:54:29 PM »
Hey Dario, ribozyme therapy consists of 'teaching' cells how to produce an enzyme that effectively blocks viral replication. So in essence you are programming your body to fight off the infection on its own. This technique would not have resistance issues, and because it has the potential of blocking all replication, I believe we will finally see how the reservoir acts in the absence of the low level replication that continues under ART.

And if the 'reservoir' turns out to truly exist in the abscence of replication, then at the very least rybozyme therapy will make meds unnecessary either permanently or on a long term basis. Then with this in place we can try clearing the latent infection with different techniques, knowing that there will be no increased viremia.

You probably read this article, it's the most recent, mainstream piece, but there is a lot of info out there on rizbozyme.

http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2006/04/07/MNGH6I59Q61.DTL
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline jupiter

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Re: Flushing out latent infection
« Reply #36 on: July 05, 2006, 07:49:19 AM »
Well all this sounds VERY  eciting indeed. I cant wait to hear the next chapter.
One question tho is hiv related dementia common? If so how common and how and when does it affect people?

Offline HIVworker

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Re: Flushing out latent infection
« Reply #37 on: July 05, 2006, 09:36:33 AM »
It is my understanding that AIDS related dementia occurs during AIDS, when viral replication occurs in an uncontrolled manner. It is thought not to occur to the same extent during chronic infection - hence the term AIDS and not HIV related dementia.
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline lydgate

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Re: Flushing out latent infection
« Reply #38 on: July 06, 2006, 12:00:50 AM »
"Not to the same extent" -- does that mean that an HIV-positive individual who doesn't meet the diagnostic criteria for AIDS (the common CDC/WHO ones) could still experience dementia? Either at a lower frequency of occurrence or a lower intensity of clinical symptoms?

Jay
Her finely-touched spirit had still its fine issues, though they were not widely visible. Her full nature, like that river of which Cyrus broke the strength, spent itself in channels which had no great name on the earth. But the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.

George Eliot, Middlemarch, final paragraph

Offline dario

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Re: Flushing out latent infection
« Reply #39 on: July 06, 2006, 12:14:12 PM »
Jay,
apparently this so called dementia affects 15-20% of us and not in the same degree.  Who, why, when and how this happens is a big unknown.  However, most agree that it progresses when a person's cd4 count falls under the 200 mark. 

Perhaps this article may help:
http://www.hivmedicine.com/textbook/hive.htm

Most of the researches say that HAART helps to diminish its effects.  Others say that it develops irrespective of HAART (see links within the article itself) or that HAART just postpones it.  Others add that if drugs manage to enter the Central Nervous System (or perhaps the brain?) dementia will be cured.

I have to admit that I was a bit scared when I've read this article.  I started thinking that I already have all the preliminary symptoms.

ciao,
dario
... when I was young, I never needed anyone, making love was just for fun, those days are gone ... Eric Carmen (Raspberries)

Offline blondbeauty

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Re: Flushing out latent infection
« Reply #40 on: July 06, 2006, 01:48:32 PM »
In Europe HIV must be different than in the USA. Two Drs. have told me dementia is no longer seen in HIv patients. Moreover, Aidsmap (british website) says it only happens when cd4 drops below 200.
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
Last CD4 count (OCT 2013): 52%= 933

Offline jkinatl2

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Re: Flushing out latent infection
« Reply #41 on: July 06, 2006, 04:54:15 PM »
the most recent fact sheet I have found about HIV related dementia is here:

http://www.emedicine.com/med/topic3151.htm

It states, in part, that:

<< The rate of HIV dementia in patients with late-stage disease ranges from 7-27%. Milder forms of ADC affect an additional 30-40% of patients. The prevalence of ADC increases 3-fold with a CD4 count of less than 200/mL and increases 7-fold with a CD4 count of less than 100/mL; however, in 4-15% of patients, ADC is the presenting clinical manifestation of HIV disease. >>

"Many people, especially in the gay community, turn to oral sex as a safer alternative in the age of AIDS. And with HIV rates rising, people need to remember that oral sex is safer sex. It's a reasonable alternative."

-Kimberly Page-Shafer, PhD, MPH

Welcome Thread

Offline blondbeauty

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Re: Flushing out latent infection
« Reply #42 on: July 06, 2006, 07:40:08 PM »
http://www.aidsmap.com/en/news/90E971EE-8A2E-4819-AAAF-AEFB43AB4CA4.asp
I prefer this version. Safe until cd4 drops below 50.
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
Last CD4 count (OCT 2013): 52%= 933

Offline Jake72

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Re: Flushing out latent infection
« Reply #43 on: July 06, 2006, 07:42:59 PM »
I asked my doctor about this, and she said that it's not something to worry about unless your cd4s are well below 200 (regardless of what your viral load may be). 

Offline blondbeauty

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Re: Flushing out latent infection
« Reply #44 on: July 06, 2006, 07:59:02 PM »
The same said my Dr. to me. In fact he said not to think about what might happen or I wouldn´t be able to live. Nobody knows what is going to happen tomorrow HIV+ or not. Two days ago a bird crashed into the left engine of our MD-80 while taking off from Geneva...If I was always thinking about what could happen...
One day I will tell you what happened when a ray hit the plane and two squirrels escaped from a cage in the cabin!
The only member in these forums approved by WINBA: World International Nail and Beauty Association.
Epstein Barr +; CMV +; Toxoplasmosis +; HIV-1 +.
Counts when starting treatment:
V.L.:80.200 copies. CD4: 25%=503
Started Sustiva-Truvada 14/August/2006
Last V.L.count (Oct 2013): Undetectable
Last CD4 count (OCT 2013): 52%= 933

Offline dario

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Re: Flushing out latent infection
« Reply #45 on: July 06, 2006, 08:09:50 PM »
In fact he said not to think about what might happen or I wouldn´t be able to live. Nobody knows what is going to happen tomorrow HIV+ or not.

Thanks Juan!  That is also what all my friends keep telling me and I think we all need this sound advice.

To conclude with an optimistic note: http://www.aidsmap.com/en/news/7BFD0A38-0C35-4804-8861-478E79E45EAA.asp
... when I was young, I never needed anyone, making love was just for fun, those days are gone ... Eric Carmen (Raspberries)

Offline HIVworker

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Re: Flushing out latent infection
« Reply #46 on: July 06, 2006, 09:21:28 PM »
AIDS related dementia can occur at any viral load and any CD4 count, but is more likely to occur when the CD4 count is low and/or the viral load is high - as commonly occurs during AIDS. There are HIV patients with minor defects in cognative function due to replication of HIV in the CNS. Increasing viral replication in the CNS causes more inflammatory response and increases the damage to the CNS causing dementia.

On another topic, a questionare designed to ask patients how they feel revealed that HIV patients scored poorly on indicators for cognative function - leading some researchers to incorrectly state that this is due to impairment of cognitive function. However, if you actually look at the questionare and give it to a depressed person they score almost exactly the same. The conclusion is that you can not always rely on the patients feelings (I feel like I have dementia) because they closely mimic depression and anxiety. If the patients were blinded to the condition that they had (ie didn't know they had advanced HIV disease) the study might be more relevant. Therefore feeling slow, having low motivation and other simple signs that some use to indicate dementia - that this is the beginning of the end. Invariably it is not and AIDS related dementia is decreasing due to HAART.

R
« Last Edit: July 06, 2006, 09:23:30 PM by HIVworker »
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline MitchMiller

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Re: Flushing out latent infection
« Reply #47 on: July 06, 2006, 10:36:02 PM »
From my own personal experience, I was suffering CNS symptoms within a year of infection.  I know my date of infection and it was confirmed by HIV neg test 3 weeks after infection, during seroconversion, then HIV+ six months later... so no doubt at all.  Around 4-6 months after infection, my brain begain to feel different when I woke from sleeping.  Can't describe it exactly, but didn't think much about it... but at 6 months, my brain began to really feel weird... like I took an expired antihistimine... then I began to have trouble verbalizing... and also began to have difficulty concentrating at work.  Finally, I got tinnitus, which I still have today, 3.5 years later.  I had tinnitus for 3 weeks during the seroconversion before it went away.. unfortunately, I believe HIV or some other opportunistic virus is still causing it in my brain.  I was a rapid progressor, developing AIDS in 10 months after infection w/TCells falling 30/month the last 3 months, until I finally started meds at TCells 112. 
I believe my case is definitely the exception, but AIDS dementia can occur even before reaching 200 TCells. 
Most of my symptoms have passed now that I've been on meds. 
Oh.. and also forgot to mention two momentary episodes of vertigo.  I nearly fell flat in the bushes when walking between buildings at work... how embarrassing that would have been... would have looked like I was drunk at work!  The other time was in the grocery store and I just hung on to the cart for dear life till it passed.  They both happened before starting meds.

Offline lydgate

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Re: Flushing out latent infection
« Reply #48 on: July 07, 2006, 01:17:30 AM »
I think we need to make a distinction between classical dementia and impairment (possibly mild) of cognitive function. But that's a whole different thread. Jay
Her finely-touched spirit had still its fine issues, though they were not widely visible. Her full nature, like that river of which Cyrus broke the strength, spent itself in channels which had no great name on the earth. But the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.

George Eliot, Middlemarch, final paragraph

Offline HIVworker

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Re: Flushing out latent infection
« Reply #49 on: July 07, 2006, 07:25:12 AM »
Well, the distinction shouldn't be that complexed. AIDS related dementia is a disorder that leads to significant impairment of brain function resulting from high viral replication in the CNS. Impairment of cognitive function is a quantifiable decrease in certain measures of cognitive function - such as the P300 cognitive test. The P300 test put simply is the brains reaction to a changing stimulus, the normal latent time being 300 microseconds. This is extended in people with cognitive function impairment. Also creatine:choline levels, measured by magnetic resonance, is another sign of inflammation of the brain that can lead to cognitive impairment. One important distinction is that I don't believe (but I can check) that cognitive impairment is a sign of oncoming dementia.

R
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

 


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