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Author Topic: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication  (Read 4405 times)

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Offline Inchlingblue

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ScienceDaily (June 4, 2009) — Latent HIV genes can be 'smoked out' of human cells. The so-called 'shock and kill' technique, described in a preclinical study in the journal Retrovirology, might represent a new milestone along the way to the discovery of a cure for HIV/AIDS.

Dr. Enrico Garaci, president of the Istituto Superiore di Sanità (the Italian Institute of Health) and Dr. Andrea Savarino, a retrovirologist working at the institution, worked with a team of researchers to study the so-called "barrier of latency" which has been the main obstacle to HIV eradication from the body.

Cells harbouring a quiescent HIV genome are responsible for HIV persistence during therapy. In other words, HIV-1 genes become pieces of the human organism, and many scientists have simply thought there is nothing we can do. Dr Savarino's team aimed to 'smoke out' the virus in order to render the latently infected cells targetable by the immune system or artificial means. They write, "This can be achieved using inhibitors of histone deacetylases (HDACs)*, which are a class of enzymes that maintain HIV latency. However, their effects on HIV are evident only when used in toxic quantities".

To overcome this problem, the Italian researchers tested a collection of HDAC inhibitors, some of which specifically target only certain enzyme isoforms (class I HDACs) that are involved in HIV latency. The toxicity of this approach, however, was not markedly decreased, although it compromises a more limited number of cellular pathways. Moreover, at non-toxic quantities, class I HDAC inhibitors were able to induce the 'awakening' of a portion of cells within a latently infected cell population. The researchers then repeated the experiment adding a drug inducing oxidative stress, buthionine sulfoximine (BSO). The results showed that BSO recruited cells non-responsive to the HDAC inhibitors into the responding cell population. An important result was that the infected cells' 'awakening' was followed by cell death, whereas the non-infected cells were left intact by the drug combination.

"I really hope this study may open new avenues to the development of weapons able to eliminate the HIV-infected cells from the body", says Dr. Andrea Savarino, "Such weapons, in combination with antiretroviral therapies, could hopefully allow people living with HIV/AIDS to get rid of the virus and return to a normal life. Of note, there are testable drug combinations composed of molecules that have passed phase I clinical trials for safety in humans". This type of approach has been dubbed 'shock and kill'. "Although this type of approach is largely accepted by the scientific community", adds Dr. Savarino, "to be honest, we have to take into consideration that some scientists are skeptical about this approach, and others even think that a cure for HIV/AIDS will never be found. Experiments using animal models will shed a new light on this difficult problem."

*Zolinza and Valproic Acid are HDAC-inhibitors

LINK:

http://www.sciencedaily.com/releases/2009/06/090604095129.htm

From THE DAILY MAIL:

"The approach has been dubbed ‘shock and kill’ because the infected cells are 'awakened' by the treatment and then die."

http://www.dailymail.co.uk/health/article-1190823/Hopes-HIV-cure-revived-shock-kill-technique-rids-body-dormant-viruses.html
« Last Edit: June 04, 2009, 04:05:47 PM by Inchlingblue »

Offline newt

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #1 on: June 04, 2009, 01:52:22 PM »
This is at a very early (test tube) stage (which does not really warrant a feature interview  >:().

People might like to read the relevant abstract:

http://www.retrovirology.com/content/6/1/52

especially the bits on cellular toxicity

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

Offline mecch

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #2 on: June 04, 2009, 03:13:57 PM »
So I turn into a 96° jello shot, but HIV free?
“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline freewillie99

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #3 on: June 04, 2009, 03:54:13 PM »
Shock and kill, huh?  Sounds a bit like "Shock and Awe" or "Shaka Zulu".

Is this deck chair material, newt?
Beware Romanians bearing strange gifts

Offline newt

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #4 on: June 04, 2009, 04:57:54 PM »
Deckchair...yer

It is perhaps tanning booth vs natural sunshine from normal outdoor activity.

The theory is you can kickstart hidden HIV into showing itself by causing an inflammatory response then kill it off (with some other agent), but I distrust the HIV virus particles and their ability/sheer bloodymindedness/ignorance of the chemical facts, and suspect there's a good chance they will evade the killing bit and slope off to hide elsewhere.  It's very hard to tell what, for example, is hiding in them lymphocytes in the brain (my brain) - - -

I await the results.

This strategy is in trial for breast cancer, but I note (1) valproic acid is a compound in the histone deacetylase class, and (2) this drug was rubbish for HIV in people. It looks more promising in late-stage cancer. Moral (perhaps): a tumour is not a virus integrated into your cell's very fabric (it's a great deal bigger, more obvious and less wily).

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

Offline mecch

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #5 on: June 04, 2009, 06:19:27 PM »
I thought HIV was written into my DNA and into me.  Its something I didn't understand about the German bone marrow cure. How did that new immune system get every last sequence, sleeping in hidden places? 
“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline newt

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #6 on: June 05, 2009, 01:27:50 PM »
erm yes

But the man in question had a blood cancer and the chemo etc killed off all his immune system, CD4s, lymphocytes, B cells etc, the places where HIV hides  (we theorise). And the HIV hiding in it it seems (we theorise). The new CD4 etc cells generated by the stem cell transplant, having no history of HIV, just got to work (we theorise). Plus there was no virus to speak off left (we theorise).

He nearly died, as many people having blood cancer treatment do.

It's a bit drastic as cures go perhaps.

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

Offline mpositive

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #7 on: June 05, 2009, 01:30:27 PM »
we theorise  :)

Offline Inchlingblue

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #8 on: June 05, 2009, 02:17:27 PM »
 The new CD4 etc cells generated by the stem cell transplant, having no history of HIV, just got to work (we theorise). Plus there was no virus to speak off left (we theorise).
 


But the whole point of this particular "experiment" was to artificially give this patient the CCR5 mutation (he already had one copy of it to begin with). They found a donor who had both copies of the mutation which made him genetically resistant to HIV that uses the CCR5 receptor.

Presumably if there was virus left in the patient's system after the transplant it would not have had a chance to take hold (if it was CCR5-tropic) since his new immune system made him genetically resistant to it.

The importance of this was as a "proof of concept" to show that it can be achieved. Now the challenge is to achieve this without necessarily destroying the entire immune system and inducing the CCR5 mutation by way of gene therapy using hematopoietic stem cells.

Freewillie's thread "I Heart Gene Therapy" (how can I do a heart on the keyboard?) discusses a recent very promising early study that further showed this is possible to do. And with a very good pedigree, Calimmune is a company started by Nobel laureate David Baltimore, whose knowledge, credentials and experience in the field of HIV/AIDS are non pareil.

They've also already recruited participants for a study at the U. of Pennsylvania in which they are using zinc finger nucleases to induce the CCR5 mutation in treatment-experienced patients.

I think when it comes to gene therapy the cat is out of the bag, so to speak. It looks to be achievable. It's only a matter of time, since it needs to be fine-tuned to a level that it can be repeated safely and effectively on large numbers of people.
« Last Edit: June 05, 2009, 09:37:11 PM by Inchlingblue »

Offline newt

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #9 on: June 05, 2009, 02:50:32 PM »
yes, the CCR5 thing is very key but also so is the no-immune-system-cos-of-blood-cancer, which seems to get lost from the story. As they said in the Bionic Man, "we can rebuild you!".

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

Offline Inchlingblue

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #10 on: June 08, 2009, 03:18:41 PM »
Here's an article about "shock and kill" from poz.com, it has some added info. not found above.

LINK:

http://www.poz.com/articles/hiv_eradication_entinostat_761_16750.shtml
« Last Edit: June 09, 2009, 01:21:04 PM by Inchlingblue »

Offline Inchlingblue

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #11 on: June 27, 2009, 03:30:49 PM »
I thought it was quite interesting, as I was reading Dr. Joel Gallant's site, that one of the Italian researchers of this "shock and kill" approach (Andreas Savarino) wrote in himself and proposed the following:

I propose you a collaboration. Let's write a protocol submit it to an ethical committee and see how the drug combination described in my paper will work in 8-10 volunteers. Having clinical data will help a lot in order to understand whether we are on the right way, or whether there is someting that should be changed.

Does this mean that there is a possibility of bypassing animal studies and go directly to humans? I hope so. It should not be too hard to find 8 to 10 individuals as willing "guinea pigs," I, for one, would do it.

LINK:

http://www.hopkins-hivguide.org/q_a/patient/recent_questions/italian_study.html?contentInstanceId=486543&siteId=7151
« Last Edit: June 27, 2009, 03:37:44 PM by Inchlingblue »

Offline xman

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #12 on: June 30, 2009, 09:05:21 PM »
Full version:

Posted on Jun 25, 2009
--------------------------------------------------------------------------------
I am the first author of the so-called "Italian study".
Dear Doctor, probably you speak like this because you're not HIV-positive. I am a physician too, but have no patients because I chose to work in the lab after getting specialised in infectious diseases. I felt it was the best way to help these people. I will continue researching in the HIV eradication topic until the final goal is reached, or, alternatively, until the day that I die.
Please, be more positive about this topic. I have no patients, but you do. So, I propose you a collaboration. Let's write a protocol submit it to an ethical committee and see how the drug combination described in my paper will work in 8-10 volunteers. Having clinical data will help a lot in order to understand whether we are on the right way, or whether there is someting that should be changed.
I will be eagerly waiting for your reply.
With best regards,

Andrea Savarino, M.D.


On Jun 26, 2009 Joel E. Gallant, M.D., M.P.H. replied:

--------------------------------------------------------------------------------
Dear Dr. Savarino,
I don't do this kind of early stage clinical research myself, but I'm sure you can find collaborators who do. I found your paper most interesting and positive, and if the tone of my response sounded negative or harsh, it had nothing to do with my opinion of your research. Since the beginning of the epidemic, I have had to temper the enthusiasm of readers who expect an imminent cure every time they read a press release reporting on a basic science experiment. It's my responsibility to inject a note of realism, given that some press releases, either due to the enthusiasm of the reporters, the insitutional press officers, the CEOs of drug companies, or the investigators themselves, exaggerate the clinical relevance of their findings. I sincerely hope that your research will lead to discoveries that will help people with HIV infection, and I wish you great success in your work.
Joel Gallant


Not surprised about the lack of collaboration between scientists and physicians.
Gallant seems not very interested. In fact he is HIV negative and so who cares.
« Last Edit: June 30, 2009, 09:09:36 PM by xman »
sign the petition launched by the aids policy project addressed to the nih aimed to increase the money needed to find the cure:

http://www.aidspolicyproject.org/petition_for_the_nih

we can make a difference and we need to fight. please support them! it doesn't cost you anything. they need it now more than ever!

Offline mecch

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #13 on: June 30, 2009, 09:09:13 PM »
Gallant seems not very interested. In fact he is HIV negative and so who cares.

Says who he doesn't care?
That's pretty harsh.
“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline xman

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Re: 'Shock And Kill' Research Gives New Hope For HIV-1 Eradication
« Reply #14 on: June 30, 2009, 09:13:42 PM »
I mean that he is not interested because he hasn't to battle with the virus. Savarino at least has empathy trying to find ways to accelerate a trial based on his findings.
sign the petition launched by the aids policy project addressed to the nih aimed to increase the money needed to find the cure:

http://www.aidspolicyproject.org/petition_for_the_nih

we can make a difference and we need to fight. please support them! it doesn't cost you anything. they need it now more than ever!

 


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