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Author Topic: Two treated with stem cell transplant with heterozygous CCR5 show promise.  (Read 3589 times)

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Offline life2

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The two "Boston patients," let's boringly call them, underwent allogeneic HSCT -- the same procedure Timothy Brown received -- but with a key difference: The stem cell donors in this case were heterozygous for the CCR5-delta 32 mutation (they had wild-type CCR5+ cells), meaning the patients' CD4+ cells still had CCR5 receptors after the procedure, leaving them susceptible to infection by any active virus that may have been lingering post-transplant.

They also -- and this may or may not be critical, we can't be sure yet -- remained on their antiretroviral therapy throughout the treatment process. In fact, as of these published results, they were still taking antiretroviral therapy long after the HSCT (about 3.5 years after in one case; nearly two years in the other).

And now, here we are:

    Proviral HIV-1 DNA levels in peripheral blood mononuclear cells dropped from 100-150 at the time of HSCT to zero within 300 days of the procedure.
    Similarly, there was no trace of HIV-1 DNA in purified CD4+ cells two-plus years post procedure -- nor was there any sign of HIV-1 p24 antigen.
    Ultrasensitive, single-copy HIV-1 RNA assays found nothing at any time point in either patient post procedure.


original article:

Offline buginme2

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This can really be interpreted both good and bad.

Good: you do not need a donor with the ccr5 mutation to eradicate hiv after a stem cell transplant.  This would open up the possibility for others to have the same outcome without searching for a specific donor that may not exist.

Bad: Timothy Browns cure had more to do with the stem cell transplant, and the wiping out his immune system and rebuilding it than it had to do with his specific stem cell donor who had the ccr5 mutation.  This leads my mind to say that the sangamo and calimune trials that are trying to change cdr5 on cd4 cells to be less likely to succeed. 

Don't be fancy, just get dancey

Offline Tadeys

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1) Wiping outthe immune system, in theory, will eliminate reservoirs. Brown had CC5 & CX4 HIV....so,  how can one explain the elimination of the CX4 HIV? In theory, the CX4 would have taken over.

2) Perhaps the host-vs-graph phenomenon is at work here too againts reservoir.

3)Read on this forum that at some university scientist manipulated CD8 cells to be (8x...?) more powerful at attacking HIV reservoirs...so, if Calimmune/Sangamo won't work ( they should in theory, but depends on % ) then perhaps supercharged CD8 cells can help.........along with other techniques....

Can you imagine if after all these years, a cure ( for some at least),  was in these cáncer drugs? It kind of makes sense: lymphoma/Leukemia drugs kill white Blood cells... HIV hides in WBC....think about it, to cure these cancers ALL of these malignant STEM CELLS cells MUST be eliminated...if not, it returns. Sooo, I am thinking that these cancer drugs might helo eliminating reservoirs.

Remember reading that Brown had whole body radiation. Did these patients also endure that?

Offline Dr.Strangelove

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That's a good question. In my opinion, the results don't look so gloomy.
First of all, the donors were heterocygotes. That means one of their two copies of the CCR5 gene was disrupted. the study doesn't say, what would have happened if both copies of the gene were intact. Would the eradication of HIV have happened anyway?
For some reason I cannot imagine that Brown and those two patients are the first HIV positive individuals that undergo a bone marrow transplant within the 30 years of existence of HIV. If the CCR5 mutation doesn't play any role in this and it's all about wiping the immune system, shouldn't there be dozens or hundreds of other Timothy Browns out there? (Or did they just never stopped taking their meds and noone knows if they actually still need them because those patients might well be functionally cured?)

Anyway, even if Mr. Brown was indeed cured by the wiping of the immune system, rather than the immunity of his new CD4 cells, still, there is absolutely no reason why introducing a defect in both copies of CCR5 and thus rendering the cells immune to HIV should not work to functionally cure an HIV infection.

Just one more thought: The recent French study of individuals that got on ART super early, during seroconversion showed that many of them were able to control HIV with their native immune system once they got off the meds. If I remember correctly many of them had consistently low viral loads, although not necessarily undetectable (!= brown).
The conclusion seems to be that when the extend of HIV reservoirs is an important determent on whether the immune system is able to deal with the infection or not. In case of the French, they could achieve the this by very early treatment but the patients did not have mutations in their CCR5 genes. But in the Timothy Brown case, the reservoirs were wiped and on top of that all new CD4 cells had no CCR5 receptors. Maybe the combination of these two things is the solution?

Either way, I hope we will see many more patients like this in the near future...

Offline OneTampa

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  • "Butterflies are free."
Can you imagine if after all these years, a cure ( for some at least),  was in these cáncer drugs? It kind of makes sense: lymphoma/Leukemia drugs kill white Blood cells... HIV hides in WBC....think about it, to cure these cancers ALL of these malignant STEM CELLS cells MUST be eliminated...if not, it returns. Sooo, I am thinking that these cancer drugs might helo eliminating reservoirs.

We have, in fact, gone down this road before.

AZT (Zidovudine) orginally presented as a cancer fighting drug, later become the first drug prescribed to treat HIV in the 1980s. It is still used today to stem mother infant transmission of HIV and to treat Leukemia.

Link: http://virus.emedtv.com/zidovudine/what-is-zidovudine-used-for.html

Still, it is good to know that medical scientists continue their work in trying to defeat the HIV virus.
« Last Edit: June 01, 2013, 08:44:34 PM by OneTampa »
"He is my oldest child. The shy and retiring one over there with the Haitian headdress serving pescaíto frito."

Offline Tadeys

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AZT was designed--in the 60s--with retroviruses in mind. One of the theories floating around back then was that retroviruses caused pretty much all cancers. It was shelved for about 2 decades and the rest is history.

I mean using hard core cancer meds...Brown was cured of his HIV before they cured his Leukemia...they had to do a 2nd transplant on him due to the fact that his cancer came back...but by his 2nd transplant, his viral load was already UD.

Most of the reservoirs are in lymph nodes. Perhaps lymphoma meds can get inside and attack these reservoirs. There are way more Leukemia/lymphoma meds then their are HIV meds...something gotta work. Even a great reduction in size will be beneficial. The following is from an interview by Alain Lafeu(sp?):

"a mathematical model, they estimate that decreasing the size of the reservoir by 2, 3 or 4 logs would delay the rebound of viremia during 100, 1,000, and 10,000 days, respectively, after discontinuation of treatment (abstract 386). So, only drugs that can reduce the reservoir at least 3 logs will be clinically useful."



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