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Author Topic: Keeping HIV Forever Dormant  (Read 4717 times)

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Offline Inchlingblue

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Keeping HIV Forever Dormant
« on: March 26, 2009, 05:21:37 PM »
Everything I've read about HIV latency has focussed on the challenges involved in activating HIV from reservoirs in order to then attack it with HAART. This sounds great since its goal, though so far elusive, is total or near-total eradication.  I've never come across any information on studies that attempt to keep HIV forever dormant in reservoirs as a possible "functional cure."

One of the articles recently cited in John's thread caught my eye because it discussed how scientists have discovered the mechanism wherein herpes virus activates after its dormancy. The article mentions,"'Now that we've identified the novel mechanism in cells that activate immune response to Type 1 herpes simplex, scientists are one step closer to creating new treatments that can activate the defence against this and other viruses,' says Dr. Desjardins. 'While it may not be possible to completely eradicate Type 1 herpes simplex in people who are already infected, at the very least, future therapies may be able to keep the virus in its dormant state.'"

Has anyone heard of any studies that are looking at ways to keep HIV forever dormant/latent after undetectable levels are reached with HAART? It seems this would be the next best thing to eradication, if it would just remain dormant in the reservoirs, hence not be wreaking havoc.

This is the link to one of the articles about herpes dormancy/activation:

http://esciencenews.com/articles/2009/03/23/herpes.scientists.find.cellular.process.fights.virus
« Last Edit: March 26, 2009, 05:24:54 PM by Inchlingblue »

Offline veritas

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Re: Keeping HIV Forever Dormant
« Reply #1 on: March 27, 2009, 08:16:15 AM »

Inch,

Here's an older article with that topic in mind:


http://www.medicalnewstoday.com/articles/100845.php

Using the gene SirT1 to shorten the life span of dormant cells.

Offline dearestgrandson

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Re: Keeping HIV Forever Dormant
« Reply #2 on: March 27, 2009, 01:47:04 PM »
I think it is because so little it actually known about these latent reservoirs. Scientists are not sure where all of these reservoirs are. They are also unsure about all of the mechanisms that keep the latent reservoirs dormant. If you put some reservoirs to "sleep" you may cause the others to become resistant to that therapy and they may become more aggressive in the area they are infecting.

http://www.aidsmeds.com/articles/hiv_cure_fauci_2042_15255.shtml

Offline Inchlingblue

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Re: Keeping HIV Forever Dormant
« Reply #3 on: March 27, 2009, 05:13:37 PM »
Thanks for the info Dearestgrandson and Veritas........great find, Veritas, I found the article you linked very interesting ;)

Offline Inchlingblue

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Re: Keeping HIV Forever Dormant
« Reply #4 on: June 11, 2009, 04:00:59 PM »
« Last Edit: June 11, 2009, 05:05:58 PM by Inchlingblue »

Offline newt

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Re: Keeping HIV Forever Dormant
« Reply #5 on: June 11, 2009, 08:51:46 PM »
Quote
I've never come across any information on studies that attempt to keep HIV forever dormant in reservoirs

Erm, combo? (this is what combo does)

- matt
"The object is to be a well patient, not a good patient"

Offline Inchlingblue

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Re: Keeping HIV Forever Dormant
« Reply #6 on: June 11, 2009, 10:48:06 PM »
Erm, combo? (this is what combo does)

- matt


LOL, I mean forever dormant BUT without having to take any meds, or maybe just taking one pill without any toxicity to keep it dormant (like Valtrex or Acyclovir with herpes).

Many other viruses remain dormant for long periods without wreaking havoc, such as Herpes and CMV, etc.

 

Offline mecch

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Re: Keeping HIV Forever Dormant
« Reply #7 on: June 11, 2009, 11:10:36 PM »
The virus is already dormant in the reservoirs, I thought. So when it wakes and replicates, HAART kills it. 

Seems like you are looking for a treatment and therefore a drug that will put it to sleep forever? So it will still be a drug, whats the difference if it is that drug or HAART?

I thought vaccine therapy was supposed to lead to natural control.  But will that be *"dormancy"?

“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline carpediem98

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Re: Keeping HIV Forever Dormant
« Reply #8 on: June 12, 2009, 04:05:43 AM »
Not to overparse the language here, but I do think that it's worth noting that HAART doesn't necessarily "kill" HIV, per se.  For the sake of this discussion, it's probably helpful to note that it merely disrupts the replication cycle of the virus, and the cell the virus has infected then functions in a sort of lessened capacity until it dies naturally and is excreted normally.  Similarly, a viral particle released from a resting cell when that cell reawakens will typically find a T-Cell to infect, and then it will be stopped from creating copies of itself by HAART (unless there isn't any HAART or unless it has somehow evolved resistance to all medicines in the combination).  Alternatively, there's a possibility that it might end up encountering another resting cell, where it will rest until THAT cell wakes up.  A final possibility is that the viral particle simply ends up being filtered from the blood and ends up being excreted harmlessly via a normal bodily function.

The next layer to this is, HIV itself isn't what goes dormant - it's not in "standby mode," so to speak - it's sitting there as active as always, but it happens to be in a cell that's in standby mode.  It's sort of a stupid passenger, bumping into things and sticking where it may, like a velcro tennis ball floating down a stream.  When the velcro encounters something suitably "sticky," it sticks.  If that something happens to be an actively replicating cell, that gives HIV the tools it needs to replicate, too.  It's just a chemical process, really - the interaction of proteins and enzymes and strands of RNA/DNA code.  If the "velcro" encounters a resting cell, then it sticks there, enters, and then has to wait until that cell switches on... then, the enzymes, proteins, etc. just do what they naturally do and start replicating using the activated cellular machinery.

I would suspect, then, that it's not likely that we'll be able to keep cells permanently dormant (and thereby keep the HIV in them permanently dormant), because ultimately the body will NEED to wake up the cells in order to summon them for duty.  The key, then, is to give the body the tools it will need to recognize uninfected "awakened" cells from infected "awakened" cells, so that those can be treated accordingly by the immune system.  This is where the stuff over in Veritas's thread, "Could this be the holy grail?" comes into play - anti-PS monoclonal antibodies could do just that, in theory.  Aside from anti-PS, which would effectively mark the cells for deletion, any alternative that would send a message to inhibit infected cells from activation would then, like HAART, have to be taken for life - because, left to its own devices, the body will naturally summon those cells for duty SOMEDAY.

Alternatively, and this is something we might see going into trials soon, we can more effectively wake up specific dormant cells and combine that with HAART in an effort to purge the body of HIV.  (I think this is noted in the lead-in to the initial message in this discussion thread.)

Since it's almost 4 AM, I may have rambled, so I'll try to wrap it up in three, tidy sentences:

Any medicine to inhibit the activation of dormant cells containing HIV will have to be taken for life, like HAART, and would require the kind of marker already being modeled in possible anti-PS treatments.  Therefore, it would seem that a strategy of induced, indefinite dormancy of infected cells would NOT be the ideal approach, as the mechanisms needed to mark cells for induced dormancy would be even more effective if used more simply and directly: as a marker for destruction by the immune system.

ADDENDUM:
The one scenario in which induced cellular dormancy would seem to be a helpful one would be this:  in a patient with an extreme resistance profile, with a severely damaged immune system.  In such patients, an anti-PS monoclonal antibody might mark infected cells for destruction, but with an immune system too weak to mount an attack, such marking might be futile.  Similarly, with few or no HAART options, activating dormant cells to "purge" latent HIV would simply result in a surge in viral replication, since HAART couldn't stop it.  In THOSE patients, anti-PS could be used to "mark" the infected cells, and a second compound could - in theory - be targeted at those specific cells to keep them from activating.  Over time (again, in theory) the patient's immune system should rebound... at which time, the cells marked by the anti-PS therapy would/should be destroyed by the resurgent immune system as the natural last-stage of treatment with an anti-PS monoclonal antibody.

All theoretical of course.

Ok, bed time.

OK, UPDATE:
I think I should already admit to being wrong about HIV itself being the dormant thing... it does have an active and a latent state all on its own... but I think many of the details of the usefulness of induced dormancy might remain.  Thoughts?
« Last Edit: June 12, 2009, 04:11:47 AM by carpediem98 »

Offline newt

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Re: Keeping HIV Forever Dormant
« Reply #9 on: June 12, 2009, 07:27:13 AM »
Mr M

Quote
I thought vaccine therapy was supposed to lead to natural control.  But will that be *"dormancy"?

Very good question

Mr C

Very good and learned post.

My only thought on waking up HIV to bump it off completely is this:

Treatment as it stands ls like putting a brick on a pile of paper in a windy room. The activate and kill strategy basically says lets take the brick off and catch the paper blowing about in the wind.  I believe there may be a safety/effectiveness question to answer. It could just turn a neat pile of paper into a mess.

- matt
"The object is to be a well patient, not a good patient"

Offline carpediem98

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Re: Keeping HIV Forever Dormant
« Reply #10 on: June 12, 2009, 09:23:39 PM »
Thanks Newt!
The metaphor I'd use for the current treatment paradigm is this:

Before HAART, you have a messy room, with paper all over the place.  Some pieces of paper remain filed away in cabinets.  You begin HAART, and the paper that's all over the place is thrown out - it's actually gone.  Then, every so often, a drawer falls open and spews forth a few pieces of paper.  HAART dutifully catches those pieces of paper while they're still in the air and gets rid of them before they can clutter up the place again. 

The idea of the activate and purge is, you get it all out of the cabinets, and then HAART, if it's still effective against the strains you have, will still be able to catch all those other pieces of paper.  Then the cabinets are empty... the room is clean... and (in theory) you won't need HAART anymore!  :)

Offline mecch

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Re: Keeping HIV Forever Dormant
« Reply #11 on: June 12, 2009, 10:21:58 PM »
Then the cabinets are empty... the room is clean... and (in theory) you won't need HAART anymore!  :)
I don't understand how the room could be completely clean if HIV is written into my DNA.  Some amazing activator is going to clean out my brain cells?
Well, anyway, its been an interesting thread.
i am hopeful. 
“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline Inchlingblue

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Re: Keeping HIV Forever Dormant
« Reply #12 on: June 13, 2009, 02:22:47 AM »
I don't understand how the room could be completely clean if HIV is written into my DNA.  Some amazing activator is going to clean out my brain cells?
Well, anyway, its been an interesting thread.
i am hopeful.  

It's definitely a challenge to "completely clean" the body of HIV, no question about that, but when you say that it's "written into your DNA" it sounds as if you see it as being in every last cell in your body and that is not the case.

HIV attacks CD4 Tcells and can lay dormant in resting or "memory" Tcells once HAART has reduced it to undetectable levels in the plasma. It is also found in a latent stage in macrophages/monocytes (and there are drugs being tested that target this). It has also been found in follicular dendritic cells. And maybe other cells as well but it is not by any stretch written into every last strand of DNA in your entire body.

There is a very interesting thread discussing the "shock and kill" technique recently employed by some Italian researchers. What they are attempting to now reproduce in animal models is what they achieved in vitro in the lab and that is to "awaken" every last cell that harbors HIV and immediately then KILL it. It's far from a done deal at this point but I bring it up as an example of one method being tried for achieving total eradication. Therapies such as anti-PS look promising, as far as targeting these cells that harbor HIV (see thread "Could This be the Holy Grail?").

HIV is not "written into" all of your DNA. In fact what is frustrating about curing HIV is that once HAART is initiated and a person becomes undetectable, the amount of latent virus that remains in reservoirs is actually a very small amount, we just have no way of getting to it at the moment since it's not active and HAART only affects virus that is active. It has been estimated that 99+% of virus is killed off with effective HAART, so we're talking only less than 1% that we have no way of reaching right now! More specifically, the number of resting memory Tcells infected with latent HIV capable of reproducing if HAART is stopped is very, very small: 0.0001%, or one out of every million!

That's why I started this thread. I was thinking that since activating that small amount of latent HIV has been such a big hurdle and challenge maybe another approach to achieving a functional cure could be to find a way to keep it forever dormant (without HAART).

LINKS:

http://www.thebody.com/content/toparts/art50467.html

http://www.aegis.com/pubs/bala/1998/BA980205.html
« Last Edit: June 13, 2009, 03:44:29 PM by Inchlingblue »

Offline veritas

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Re: Keeping HIV Forever Dormant
« Reply #13 on: June 13, 2009, 04:50:27 AM »

Inch,

Somewhat relevant:

http://www.pnas.org/content/106/15/6321.full

I think you will find the above interesting.


v

Offline elf

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Re: Keeping HIV Forever Dormant
« Reply #14 on: June 13, 2009, 10:49:04 AM »
I don't understand how the room could be completely clean if HIV is written into my DNA.  Some amazing activator is going to clean out my brain cells?
Well, anyway, its been an interesting thread.
i am hopeful.  
DNA is written only into your infected cells (mainly CD4 cells and monocytes), so they will be killed by therapy, new cells created by your immunologic system will be HIV-free. Similar to cancer therapy: cancer-contaminated tissue is killed so only cancer-free cells remain.

As for the killing resting cells, I like this approach:
http://www.thebody.com/content/art51696.html
« Last Edit: June 13, 2009, 10:51:43 AM by elf »
I got GRID on GRInDr

Offline Inchlingblue

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Re: Keeping HIV Forever Dormant
« Reply #15 on: June 13, 2009, 01:30:17 PM »
Inch,

Somewhat relevant:

http://www.pnas.org/content/106/15/6321.full

I think you will find the above interesting.

v

Very interesting! It's heartening that we are now at a point as far as the research (now that we have reached the functional limits of HAART), that serious efforts are being made toward achieving total eradication.

 


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