Germans 'cut HIV out of infected cells'

[GoForIt]

http://www.thelocal.de/20131218/germans-cut-hiv-out-of-infected-cell-dna

German scientists have managed to remove HIV from cells while leaving those cells alive - opening the door to potential cures for the disease.

Biomedicine researchers at Dresden's Technical University succeeded in curing several HIV-infected mice with the new method which uses an enzyme to cut the virus from the DNA of infected cells.

"There are various methods and similar approaches, but removing the virus from infected cells is unique," said Professor Joachim Hauber, head of the antiviral strategy section at partner research institute, Hamburg's Heinrich Pette Institute.

He said this approach was the only one so far which could actually reverse an HIV infection, leaving the treated cells healthy.

Whether this would function with people could only be established in clinical trials, he said, for which the money is not yet available.

Dresden team leader Professor Frank Buchholz said the 'molecular scissors' could be ready to use in ten years - as a somatic genetic therapy (using a patient's own gentically altered cells).

"Blood would be taken from patients and the stem cells which can form blood cells, removed," he said.

Laboratory work would introduce the crucial HIV-cutting enzyme into the stem cells, altering their DNA. They would then be put back into the patient.

The theory is that the genetically altered immune cells would reproduce, cut the HIV from infected cells - enabling them to function again.

This was the effect seen at least in part, among the mice.

"The amount of virus was clearly reduced, and even no longer to be found in the blood," said Hauber.

President of the German Aids Society, Professor Jürgen Rockstroh said he hoped funding could be found for further work on the approach.

"It is one of the most exciting things of all," he said. "There is a vague hope of cure, but that must first be proven."

The Dresden team have managed to create this enzyme - via mutation and selection - so that it identifies HIV.

"The HI-pathogen is a retrovirus which gets into the genetic substance in DNA," said Buchholz. Certain recombinase-class enzymes can cut up the DNA double helix and put it back together again in a different pattern.

The researchers have managed to manipulate the enzyme so that it can identify a particular sequence and remove it - and they say it is more than 90 percent effective in identifying the HI-virus in this way.

Hauber said the deciding phase, of bringing the approach to treating people in clinical studies, would be difficult in Germany.

"The potential is not being used," he said, claiming that pharmaceutical companies have until now shown little interest in investing in potential cures for Aids.

He and Buchholz said they would be looking for sponsors and public money for their future research.

[Dan0]

"The potential is not being used," he said, claiming that pharmaceutical companies have until now shown little interest in investing in potential cures for Aids.

He and Buchholz said they would be looking for sponsors and public money for their future research.

Very interesting!  That one paragraph - while not unexpected is certainly sad!  I think that its nothing that I didn't assume before but its just, well, simply shocking to actually see it in print staring you in the face.

[Tadeys]

Why 10 years? Next Step after animal trials is human trials. This has worked on rats.  This could be used in 6/7 years if clinical trials start today.

[GoForIt]

The article says they need funding to test in clinical trials on humans and they don't have that funding yet so they are looking for sponsors to get the money.  I agree with you, these types of clinical trials should start immediately for the sake of man kind.

[Dr.Strangelove]

Why 10 years? Next Step after animal trials is human trials. This has worked on rats.  This could be used in 6/7 years if clinical trials start today.

No, it's not ready for humans yet, there's some more hurdles to take. The main problem is: how to get the Tre-Recombinase (the 'molecular schissor') into the infected cells. In the mouse trials they used transgenic mice that already had the artificially constructed Tre-Recombinase gene included in their genome. So, every cell that got infected with HIV could then activate the gene right away and cut HIV out of the host genome.

[JazJon]

It seems like cure news stories are building more and more, one approach has to work eventually!   

(saw this thread was already started) Here's another link to the same news.
http://news.sudanvisiondaily.com/details.html?rsnpid=230303

[xinyuan]

This was successfully done in a mouse model. Not human samples, much less human beings. Very few "cures" that succeed in animals see any effective hope in humans.

For the sake of argument, suppose they do get the gene sequence inserted into stem cells AND get successful enzyme production? A human immune system will likely recognize the enzyme as foreign, form antibodies, and shut it down before it can do anything.

Assuming that hurdle clears, "claiming" it will recognize the viral DNA 90% of the time AND in human cells is very different than "proving."

And if it does cut the DNA as planned, the cell has to repair itself and/or die. I'd much prefer the latter. Why? Because the possibility exists for the cell to repair incorrectly. Read possible mutation. Then, whether the mutation is harmless or leads to a cancer or autoimmune disorder ...

Too many hurdles, too many safety issues.

10 years? I say at least a lifetime, if not generations, of work left for this route.

[Tadeys]

Xinyuan....ahhhh, the rats probably had humanized immune systems. And it seems to work. Science has advanced so much since the 80s/90s that much more BASIC science breakthroughs are going to work at the clinical level. I'm not a scientist with a Ph.D, I'm just a medical doctor....I am sure a cure of sorts will be found soon, not in generations.

[Dr.Strangelove]

For the sake of argument, suppose they do get the gene sequence inserted into stem cells AND get successful enzyme production? A human immune system will likely recognize the enzyme as foreign, form antibodies, and shut it down before it can do anything.

And if it does cut the DNA as planned, the cell has to repair itself and/or die. I'd much prefer the latter. Why? Because the possibility exists for the cell to repair incorrectly. Read possible mutation. Then, whether the mutation is harmless or leads to a cancer or autoimmune disorder ...

Too many hurdles, too many safety issues.

I don't think there will be an issue with the enzyme being recognized as foreign, although I am not 100% sure. The enzyme would not be released into the blood stream. It would only be expressed within the infected cells (and only those!). That is because it uses HIV's own TAT as a kind of transcription factor. Without TAT, the enzyme will not be produced.

In terms of DNA repair (which is indeed a serious problem), the recombination approach is as safe as it gets. Unlike the zinc finger or other techniques, the recombinase does _not_ produce free DNA double strand ends (which are dangerous). In the recombination event the recombinase cuts HIV out and reconnects the ends, all in one step.
Having a gene therapy with zinc fingers (which Sangamo got permission for but I think hasn't started yet) is much more risky, since they produce free DNA ends and you cannot simply switch off the enzyme once the patient underwent the gene therapy.

The scientists who are working on this approach recognize that their solution will only work in combination with other techniques (although I believe this is true for most cure approaches). They once mentioned that it may be necessary to use drugs that purge the reservoirs in cooperation with their Tre-recombinase.

One more addition, not mentioned in the article: The Tre-recombinase that they engineered right now works only for subtype B. They are working on others as well but they are not ready yet.

[xinyuan]

Xinyuan....ahhhh, the rats probably had humanized immune systems. And it seems to work. Science has advanced so much since the 80s/90s that much more BASIC science breakthroughs are going to work at the clinical level. I'm not a scientist with a Ph.D, I'm just a medical doctor....I am sure a cure of sorts will be found soon, not in generations.

That's why I hate news bytes. They provide nothing of the actual research being done.

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003587

If you're referring to the current pharm model, the translation rate to humans is still very low. As one medical person to another, we should be cautious over assuming anything in the research world not yet in the clinical world. Even with the mice having humanized immune system, their overall biology is still very different from actual humans. Even other researchers caution that success will hinge on actual tests in humans.

Dr. Strangelove, thank you for correcting me. The Tre-recombinase does appear to stay intracellular. What's to say the patient's own immune system won't recognize the modified cells as foreign or at least compete with them?

I imagine that we will have to await another Berlin patient situation.

But, still. This is interesting. It is a direct competitor to the Sangoma CCR5 model.

[Tadeys]

I was going to link the following info yesterday but got lazy. CRISPr is the best thing to come along in over a decade. You can pretty much get rid of Zinc fingers, Tre...these are nowhere as efficient as CRISPR....and they are already working on HiV provirus with it: http://www.nature.com/srep/2013/130826/srep02510/full/srep02510.html


Xinyuan, when I say a CUre of sorts, I think we will have a combination of therapies working before a single therapy....with all that I have read during the past 2 years in BASIC science, I truly believe we will start seeing some things happening soon( 5-7 yrs), albeit with a low success rate at first...until it gets tweeked-up or some other breakthrough comes along and helps with the End Play or coup de grace...(Spelling?)


Cheers

Oh, and do some research on CRISPR....it is amazing, and not just for HIV!!

[Tadeys]

Xonyuan, Don't want you to counter with a viral vector claim... , so voilà, the breakthrough Gen Therapy was hoping to find: http://medicalxpress.com/news/2013-12-gene-therapy-method-tumor-blood.html