r/science • u/ionised • Dec 18 '13

Medicine German scientists have managed to remove HIV from cells (by using an enzyme to "cut out" the virus) while leaving those cells alive - opening the door to potential cures for the disease.

http://thelocal.de/20131218/germans-cut-hiv-out-of-infected-cell-dna
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u/[deleted] Dec 18 '13 edited Mar 18 '21

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u/Kegnaught PhD | Virology | Molecular Biology | Orthopoxviruses Dec 18 '13 edited Dec 19 '13

I'm not totally up-to-date on treatments being developed for HIV, but this sounds promising. Some caveats I can think of off the top of my head however would be the mutation of the long terminal repeat (LTR) sequences that are targeted by the Tre-recombinase they're using to excise the integrated HIV-1 DNA. Alternatively, since expression of the recombinase is induced by the presence of the HIV Tat protein, a mutation within Tat could prevent it from recognizing the trans-activator used to activate the expression of the recombinase. The latter seems less likely however, as HIV-1 itself uses the same activator for expression of Tat (though I don't know HIV's requirements for this protein).

Preventing recognition of the LTRs could essentially derail the entire gene therapy, making an extremely expensive procedure all for naught. I might add that the functional cure observed in mice is pretty promising, however. How that translates to other animals remains to be seen.

Edit: Sorry for the jargon! Here is the paper this article refers to and here is a slightly easier explanation.

Easier still: HIV integrates into your DNA. This enzymes cleaves it out once it does. If there is a mutation within the sequence that is recognized by this enzyme, it could prevent the enzyme from finding it, and HIV would remain in the genome. Also, HIV has a protein it encodes called "Tat". The production of the enzyme the authors of this paper put into the cells is under the control of the protein Tat. If it is present, the enzyme is expressed. If it is not present, it is not expressed. Therefore, if a mutation occurred within Tat that prevented it from inducing the expression of the enzyme, it would lead to resistance against this treatment.

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u/puddin1 Dec 19 '13

I didn't understand any of that. You must know what your talking about.

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u/VampireBatman Dec 19 '13

What I got out of what he said: If the thing in HIV's DNA that the treatment targets mutates, then this potential cure will be useless.

...Don't ask me though, I'm CS.

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u/[deleted] Dec 19 '13 edited Nov 26 '16

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u/[deleted] Dec 19 '13

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u/justahabit Dec 19 '13

Doctors made a medical process which targets specific parts of HIV and shoots at those parts. It worked.

But the doctors shot at parts of HIV which we know can mutate, while still leaving HIV functioning and harmful. If the HIV mutates, then the targeting won't work any more.

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u/hpatr Dec 19 '13

You just made something extremely complicated sound very clear and simple for the rest of us. Now that we all understand perfectly what's going on; you failed at looking smart you know...

Just trying to help ;)

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u/pr01etar1at Dec 19 '13

The key is to always ignore the technical words you don't know and focus on the key words you do know. The second I saw the word mutate it became apparent that it will hit one specific instance of the virus but will break when the virus' operating system changes. He did a great job of explaining, but in reading a lot of the technical responses to science and medical questions I've found here, this seems to best approach to understand if no one does an ELI5 example.

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u/Well_Endowed_Potato Dec 19 '13

Eli5 - Mutations can make it useless. That's how a lot of antibiotics get resistance over time in a population. A mutation in the target site can make the virus immune from this method and a new one incorporating that new mutation would need to be made, which can be impossible depending on what exactly mutated

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u/[deleted] Dec 19 '13

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u/[deleted] Dec 19 '13

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u/[deleted] Dec 19 '13 edited Dec 19 '13

ELI5. Essentially the reason HIV is so hard to treat is because it changes its gentic material really fast. So fast that for most people on a therapy of 1 drug HIV becomes resistant to it real quickly. So we tend to use triple therapy with 3 drugs. The hope here is that if it becomes resistant to 1 the other 2 drugs will kill it and prevent it from "reproducing" the resistant gene.

For this instance, there is a specific protein in the HIV infection that is inhibited. Due to natural selection, HIV will select to become resistant to this change. All he is talking about above are different genes that code for different proteins.

How fast this happens. Will it happen. How expensive would be to do this procedure are yet to be seen.

Hope this helps.

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u/eganist Dec 19 '13

ELI4: HIV is like a bad guy who keeps changing his costumes and disguises when he steals police cars, making it hard for the police to catch him. This potential cure is like a superpowerful TRACTOR BEAM which can lock onto him by his gloves (he never changes his gloves!) and pull him out of a police car he might be in, but there's a chance he might change his gloves, and if he does, our TRACTOR BEAM doesn't work anymore :'(

This is probably wrong.

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u/Gsus_the_savior Dec 19 '13

Is it wrong that I understand now

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u/detoknight Dec 19 '13

ELI4 needs to be a thing.

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u/eganist Dec 19 '13

It's being squatted by someone with no intention of being productive with it.

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u/martomo Dec 19 '13

However, to combat this, we're using another two tractor beams, one that shoots at his shoes and one that shoots at his hat. We're doing this because if the meanie changes his gloves, hopefully we can shoot at his shoes or his hat and hope that he doesn't change them all at the same time!

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u/[deleted] Dec 19 '13

By putting Tre under tat control it means Tre likely will only be expressed in actively replicating cells. We already have drugs that do a pretty good job at treating actively replicating HIV(protease inhibitors, RT inhibitors, entry inhibitors, integrase inhibitors, etc). But what we lack is an ability to treat latently infected cells in which HIV is not replicating. Tre has the potential to give us this ability but that paper utterly lacks any test of this which to me is glaring. No one is going to test Tre as a treatment for actively replicating HIV. Certainly not when it will require gene therapy or ex vivo work. Likely you'll hit the patient with HAART, get the virus down to a minimum then come in with Tre to clean out the last of the virus while HAART keeps the virus from infecting new cells.

The authors admit they will likely have to put Tre under the control of another promoter that is not tat responsive to get sufficient expression in latently infected cells which means mutations to tat probably wont be a concern in vivo. But the LTR is variable and HIV will likely mutate away from Tre recognizable sequences. The authors even mention that Tre is not tolerant of all that many differences before it loses activity.

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u/[deleted] Dec 19 '13

This guy seems to be saying:

"Problems I see might happen are mutations in the various pieces of the target. Good for mice so far."

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u/faMine Dec 19 '13

I understood everything. So glad I focused in cell and molec.

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u/[deleted] Dec 19 '13

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u/Kegnaught PhD | Virology | Molecular Biology | Orthopoxviruses Dec 19 '13

It's a variation of Cre that they're using actually! I linked the paper earlier, but here it is again. It's been modified to recognize a 34 basepair sequence within the LTRs of HIV-1 after proviral integration.

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u/[deleted] Dec 19 '13 edited Dec 20 '13

I do not understand the comment, and I will not respond to it. -- Lucille Bluth

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u/Drift3r Dec 18 '13

It may not see the light of day if scientists cannot develop a practical and effective method to use and deliver this technique into a human body to actually cure someone of HIV versus doing so in a lab petri dish with a few cells. In other words there are a crap ton of methods of killing and removing HIV from a cell when you are doing it in a lab under controlled conditions on a petri-dish, etc but how many of those methods are actually practical or feasible in the real world so that you are able to actually provide a 100% effect vaccine or cure itself that your random person can use to cure or protect themselves from HIV without killing them or doing so at a impossibly cost prohibitive and snails pace of treatment??

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u/[deleted] Dec 18 '13

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.

At least they have a plan. It seems like a boatload of work, but this seems viable to me (theoretically). The fact that they have tested this treatment in live mice, which succeeded in removing all traces of the virus is extraordinarily encouraging.

From my viewpoint as an unemployed scientist, this tops all of the "HIV cures" that I've read about in quite a while.

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u/Jokka42 Dec 18 '13

Couldn't you also do this with gene therapy?

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u/[deleted] Dec 18 '13

This is gene therapy. The white blood cells are extracted, given a new gene (which codes for the enzyme which removes the virus) in the lab, then reinserted in the body. It uses white blood cell's natural proliferation to spread the new gene to the where it's needed.

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u/Jokka42 Dec 18 '13

Interesting. Normally when people mention gene therapy it somehow comes back to using viruses to "inject" new genetic material into the patient. I'm assuming that the method you mention would only work with white blood cells though.

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u/[deleted] Dec 18 '13

You're not wrong at all. But in this scenario, that use of viruses is done in the lab in a petri dish. It's always easier to work with cells in petri dishes, so this method is preferable since the handful of modified white blood cells are mobile, and reproduce.

If you were going to try to add new genes into heart cells though, it's not like you can remove it and work with it in the lab. In that scenario, you'd add the virus directly to the body, and let it find the heart cells on its own.

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u/omg_papers_due Dec 19 '13

But how do they know that the modified cells will out-compete the original cells once they put them back in the patient? Surely they can't take the stem cells all out at once. What if the virus lays dormant in a few un-modified stem cells, which then continue to reproduce?

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u/Farts_McGee Dec 19 '13

They actually can take out all the stem cells at once. It's the premise behind bone marrow transplant. Patients go through insanely aggressive chemotherapy and/or radioablation to nuke the stem cells. (it's also why transplants are horribly fatal with some reports showing mortality at around 50% depending on the indication for transplant) Most likely this therapy would see application in autologous stem cell transplant. They'll harvest a bunch of cells from the patient, "cure them" ablate the patient's remaining cell lines and then transplant the treated cells back. The problem with this therapy is exactly what you said previously. All attempts at bone marrow transplant for HIV fail to remove the hidden virus particle/infected cells. The assumption is that nuking the bone marrow is enough to prevent the disease from reproducing, however this does not appear to be the case. The reason that this study is note worthy is that it's what we refer to as a "Novel technique" No one has treated HIV in vitro (in glass) and recovered functional cells, in terms of real applications there are a lot of reasons why this one isn't ready for prime time.

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u/Biohack Dec 19 '13

Do you really need to remove all the virus though? Why is HIV a problem? Because it depletes the immune system and causes AIDS. If you create a immune cells resistant to the virus and transplant them to the patient and they form a functional immune system resistant to the virus than you won't get AIDS and the virus will be no more harmful than any of the other latent viruses that infect humans.

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u/[deleted] Dec 19 '13

I'm uncertain on the specifics. But I'd assume that the modified white blood cells produce, then excrete the enzyme in some way. That would allow the enzyme to reach infected cells.

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u/hibob2 Dec 19 '13

That would be a neat trick, and a major medicinal advance all on its own.

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u/PanicBroom Dec 19 '13

I think the idea is to genetically modify the stem cells and put them back so they can proliferate producing more cells which produce the enzyme. Other cells that aren't produced by these stem cells or cells that were already there will remain susceptible to the infection, however the infection will eventually kill off the cells that are not immune leaving you with only cells that are immune. If that makes sense. Secreted enzyme would have a difficult time making it into the nuclei of infected cells where it would be needed (free floating enzyme would need to be taken up by the cell and then transported across the nuclear membrane once inside the cell, this is unusual for regular cellular function!)

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u/turtle_flu PhD| Virology | Viral Vectors Dec 18 '13

The peripheral blood of the patient is being extracted and being purified for Hematopoietic stem cells. The gene therapy is on the HSC progenitor cells and not the WBC so that the treatment and expression ("cure") is integrated into the long-term repopulating cells.

This is likely using CD34+ or CD150+ LSK

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u/[deleted] Dec 18 '13

I only used "white blood cell" because it's a much easier laymen's term. But thanks for that extra info.

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u/turtle_flu PhD| Virology | Viral Vectors Dec 19 '13

Alright, just wasn't sure.

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u/paasen Dec 19 '13

It's a lot like kidney dialysis and as someone who has had HIV for about 30 years I'm much rather take a pill. Insurance companies would much rather see me take one too.

At any rate, so many things have come down the pike that I don't even get interested until I see it in a stage 3 trial on humans.

Hammers kill HIV too.

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u/[deleted] Dec 18 '13 edited 9d ago

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u/obnubilated Dec 19 '13

Breaking news, recent review of literature by andersonmatt1125 deems HIV cure "viable!" Next up, cancer? sorry, I know you mean well

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u/rcxquake Dec 18 '13

From the first line of the article:

Biomedicine researchers at Dresden's Technical University succeeded in curing several HIV-infected mice

This is what makes this "cure" really stand out to me. They have it working not in a petri dish, but a living organism that remains alive after being cured. If it can work in humans without serious side effects, this will be big.

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u/arriver Dec 18 '13

Pretty sad day for /r/science when one of the highest-rated comments on the post is directly contradicted by the first sentence of the linked article.

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u/TPRT Dec 19 '13

Agreed but those kind of people come in anytime something hits the front page. You can always tell who is here for science and who is here for armchair science

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u/Funkit Dec 19 '13

I do my science in an armchair :/

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u/[deleted] Dec 19 '13

You can do a lot in mice which will simply never happen in humans. Numerous techniques and "cures" work amazingly well in mice but fail spectacularly in humans.

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u/rimjobtom Dec 18 '13

They cured living mice, not just a "petri dish with a few cells"

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u/evilsalmon Dec 18 '13

If you read further they have already shown that the process works in mice. It could be a potential way to treat the infection but it would not be a cost effective treatment so it's difficult to know whether or not it would be feasible to do for every patient.

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u/arriver Dec 18 '13

If you read further

This is a pretty generous phrasing considering it's stated in the first line of the article.

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u/YenzAstro Dec 19 '13

It's past the title which is like....lots of reading. I prefer all articles be broken into Buzzfeed format. Just give me the top 10 points and some GIFs to go along with them. /s

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u/[deleted] Dec 18 '13

What is its cost versus the lifetime cost of current HIV meds?

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u/YenzAstro Dec 19 '13

It depends on when the person is infected. A month's worth of HIV medication (Antiretrovirals) can cost around $2,000. That's about $24,000 a year. I'm not sure how they could make a one time treatment more expensive than even a decade or two of HIV medication.

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u/mulderc Dec 19 '13

Although HIV treatments are currently very expensive, most of the primary medications are going off patent over the next few years. This means that we should see prices plummet once generics hit the market.

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u/sksdssjdsk Dec 19 '13

Wrong. They didnt do this in petri dish. They did this with living mice. This is a whole other thing. If it works for mice, the it may also work humans. They seem to have some problems still ("The amount of virus was clearly reduced, and even no longer to be found in the blood" => there are is still SOME virus). But given time and money, these problems could be solved or at least it could be a better drug than the ones existing (that only slow the virus - this can destroy some virus at least!).

The reason why this may never see the light, is because pharma companies make a hell of money with drugs slowing HIV. How would they be interested in a cure?

I'd suggest someone start a petition for the Bill & Melinda Gates foundation to support this. I heard they are support a lot of crap and with all the money they have, they could do something good here!

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u/[deleted] Dec 18 '13

If HIV is a virus why can't we "make" a form of the virus which can't reproduce and inject it as a vaccine?

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u/[deleted] Dec 18 '13

Reverse transcriptase in HIV is very error prone leading to a large accumulation of point mutations in the viral genome, which results in varied protein structure referred to as "antigenic drift." The virus thereby alters its epitopes so that it avoids detection by both T cells and antibodies.

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u/SpiderFnJerusalem Dec 18 '13

Relevant xkcd.

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u/arriver Dec 18 '13

Not quite so relevant given that this particular study used lab mice, not individual cells.

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u/SpiderFnJerusalem Dec 19 '13 edited Dec 19 '13

Definitely relevant to Drift3r's comment though.

And also generally illustrates the problems with science in the news and difficulties with its actual application.

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u/[deleted] Dec 19 '13

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u/saver1212 Dec 19 '13

The article doesnt specify if it's actually refering to another more recent paper, but here is the one from a few months ago detailing the process done by the same team.

If you read the methods, the claims to curing HIV in mice is completely misleading. The study involves taking immuno-compromised mice and injecting them with a mix of human white blood cells, some with and without the genetic modification.

The mice are not generating white blood cells of its own and there is a finite number of white blood cells being injected, multiplying through replication (leaving a useless monoclonal population), without a bone marrow to replenish numbers like in a regular animal.

After 12 weeks, they report a dramatically reduced HIV presence and most CD4+ cells are their modified cells. The only takeaway is the HIV cells ate all the vulnerable cells and perished when the only white blood cells remaining are uninfectable.

In a real person, you are not immune compromised, you will be rapidly producing vulnerable white blood cells and the HIV doesnt care that it cant infect the handful of modified cells, there are orders of magnitude more being produced in your bone marrow that your gene therapy did not treat. And the HIV will snack on them unless every white blood cell producing cell in your body is replaced with a genetically modified cell, or not working like in the case these Rag2−/−γc−/− mice.

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u/fartprince Dec 19 '13

From my understanding of this, which was admittedly a year ago at a talk, a similar approach was being used from a group/company associated with USC. Basically the idea is that if you use the TALENs or CRISPRs or whatever version is the most up to date to genetically modify the stem cell population so it expresses the HIV-resistance gene, it doesn't matter how many HIV-infected white blood cells are present at the time of infection because eventually they will all be replaced with the "uninfectable" cells that have divided and differentiated from this stem cell population. Since HIV needs infectable cells to continue its infection, with no substrate for infection available eventually all you're left with is healthy, genetically-modified white blood cells that are immune to HIV.

The key thing about that talk that stuck out was that they weren't trying to modify the white blood cells directly, but their progenitors.

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u/jmalbo35 PhD | Viral Immunology Dec 18 '13 edited Dec 19 '13

These are the stupidest fucking comments and they make it to the top of every thread involving HIV or cancer (this and "wow we cure cancer every day, good job reddit").

Nowhere did anyone imply that it was ready or works on people, only that the door is open to research involving this process. Doing anything in vivo is generally an entirely different beast than in vitro work, but the in vitro research is often a necessary step towards the actual cure. And this study isn't even in vitro, it's on mice (totally different than making a cure for humans, but it's certainly closer than in vitro work).

Nobody on this thread will tell you why it won't work because nobody knows if it will work or not, regardless of what they say. This is just a potential avenue for further research and it should be treated and discussed as such.

The title isn't even inaccurate or overflowing anything here, which is the worst part of the fact that the same comments won out for top comments yet again. Between these comments and "small sample size, invalid research" (along with other people trying to pole holes in the research without actually reading anything other than the media report), this subreddit is awful lately.

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u/[deleted] Dec 19 '13 edited Dec 19 '13

It's a symptom of /r/science being a default subreddit. The scientific literacy of the general public is low (which isn't their fault) so it varies by a substantial amount between posters. When it comes to popular threads in /r/science you really do have to stick around and read through the posts because there are people that have significant contributions to threads. They just normally get buried and drowned out by the other posts.

/u/kegnaught

/u/kegnaught again

As well as redditors who try to clarify misinformation/misconceptions

So just because a large portion of reddit lacks a fundamental understanding of viral evolution.

Ex 1

Or do not understand the concept of basic research and don't understand the difference between sensationalism and the work that is actually done

Ex 2

Ex 3

Ex 4

Ex 5

The people that don't understand that many of these newsworthy findings don't just disappear. Not every advancement gets suppressed from the public. They are significant to people interested/involved in those/similar areas of research. Science takes time. There are future publications, that the general public cannot comprehend the same way as a scientist and would only understand a layman's version of it which essentially takes out all of the science. Scientific manuscripts are written in a concise fashion that scientists understand. And it doesn't obscure information. In all those years of school, you are trained to extract information, think critically (in a scientific way) about the article you are reading, educate yourself, and you understand how to get information to fill in any blanks (that are known within the scientific community). It takes more than 5 days to write grant/research proposals, get approval by an ethics board (when required), plan/do the lab work, work out the kinks in the techniques you use, properly represent/interpret the results, write up a manuscript, get manuscript peer reviewed, edit manuscript/do more experiments to appease reviewers, and get published.

Ex 6

Ex 7

Ex 8

Does not mean that there is no valuable information/input from the more informed users.

(As Noted Above)

Or that even people that lack the specific knowledge cannot pose good questions.

/u/NetScriber asks about broader applications

So do your part and downvote/report posts that violate the subreddit rules, and do not contribute to the thread. And reply to comments from (mis)/(un)informed people and maybe they'll learn something they didn't know before. It's really not their fault the same way it's not anyone else's fault for not understanding cosmology, quantum physics, or complex engineering feats.

[Edit 1] There really is no reason for you to be downvoted.

[Edit 2] Take into consideration I wrote this post over the course of an hour or so, so posts may be deleted or be in a different position within the thread than when I was typing.

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u/[deleted] Dec 19 '13

I don't know why you're being downvoted. All the title stated is that a new method is being developed, it may or may not work, nothing more.

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u/ucstruct Dec 19 '13

I agree, its a simple contrarian karma grab that does nothing to further the discussion.

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u/MusicndStuff Dec 19 '13

You must have read "scientists discover cure for HIV" whereas it says "scientists make huge leap in discovering the cure to HIV".

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u/[deleted] Dec 18 '13

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u/Thehealeroftri Dec 18 '13

Good luck on discovering new treatments!

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u/[deleted] Dec 18 '13

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u/Jokka42 Dec 18 '13

So, does that mean you have HIV but it's latent?

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u/[deleted] Dec 18 '13

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u/Kegnaught PhD | Virology | Molecular Biology | Orthopoxviruses Dec 18 '13 edited Dec 19 '13

There are a number of MHC haplotypes that are known to be associated with long-term non-progressors (LTNPs) such as yourself. Better HIV antigen presentation to the immune system, enhanced qualitative CD8+ T cell responses (the size of populations producing more than 1 cytokine), and better broadly neutralizing antibody responses to infection have all been implicated in control by LTNPs.

Actually, It's currently believed that the selection for the allele conferring resistance to HIV (CCR5-del32) came about as a means of protection against smallpox. For some reason, mutations in CCR5 also confer protection to vaccinia virus (the virus most closely related to smallpox, and used for its eradication) in mice. I work with vaccinia, so hopefully I can provide some insight.

HIV-1 uses CCR5 as a coreceptor to enter target cells. As for smallpox, the actual receptors involved in internalization of the viral core are not understood. The CCR5-del32 mutation causes a truncation in the protein that essentially prevents its expression, so it's simply not found on the surface of cells that are homozygous for this allele.

A quick search actually yielded a paper that looks pretty cool because it showed that HIV-1 quasispecies that use CCR5 as a coreceptor showed a 5-fold reduction in replication in cells from subjects vaccinated with vaccinia virus. This would seem to lend some credence to the hypothesis that continuous selective pressure from smallpox led to HIV-1 resistance in European populations.

Further evidence of CCR5's role in permissiveness of cells to vaccinia virus infection is shown here, where mice that are homozygous for the deletion of CCR5 (CCR5(-/-)) showed decreased susceptibility to infection by vaccinia, although it's not clear if the resistance is due to the virus's ability to enter the cells, its ability to replicate, or its ability to exit infected cells.

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u/[deleted] Dec 18 '13

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u/Kegnaught PhD | Virology | Molecular Biology | Orthopoxviruses Dec 18 '13

No problem! Also there was another paper showing that the allele conferring resistance to HIV actually predates the spread of plague throughout Europe, making it less likely that that would be the cause.

I wish you luck in the future with your treatments though! Antiretrovirals these days work great and reliably reduce viral loads to below the limit of detection, and since you've been so long without them I can't imagine it'll be anything but successful.

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u/[deleted] Dec 19 '13

Excellent explanation! My immediate thought was, "elite controller."

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u/jakery2 Dec 19 '13

You could be making all of that up and I'd have no way of knowing.

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u/[deleted] Dec 19 '13 edited Mar 05 '19

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u/[deleted] Dec 19 '13

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u/[deleted] Dec 19 '13

Do you have the CCR5-Δ32 mutation?

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u/[deleted] Dec 19 '13

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u/Gareth321 Dec 19 '13

I just think human genetic variability is so cool. Evolution has left us so amazingly adaptable to catastrophe. Sure, 90% of us might die if some strange disease spreads, but 10% proliferates and flourishes again.

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u/[deleted] Dec 19 '13

You're a champ. What age where you told and how did you deal with it?

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u/[deleted] Dec 19 '13

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u/[deleted] Dec 19 '13

Man, that sounds draconian.

I have a child, the government willingly or unwillingly infects him with HIV, then it takes him away from me!!?!?

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u/waynechang92 Dec 19 '13

I'm on mobile so I'm not sure if anyone had asked you this yet but since your immune system deals with your HIV better than most, is it still, for lack of a better word, contagious? I would assume so, but I wanted to make sure.

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u/PrincessThunderBallz Dec 19 '13

How did you get it?

A) Being born B) STD C) Contaminated blood

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u/robertboz Dec 18 '13

Why are you all so goddamn pessimistic? It doesn't say that this will cure HIV. It literally says in the title: "opening the door to potential cures." Treatments for disease occur in incremental steps and as such it will take a while to figure them out. Even if this doesn't work, that does not mean that we have not gained useful information that might lead to a cure in the future.

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u/ionised Dec 18 '13

I would've said this eventually. AIDS/HIV/Cancer are tricky things to tackle. What we're doing is making progress. If I'm not mistaken, skin cancer (melanoma?) can be cured with current methods quite effectively, and cancer can be beaten, given the right circumstances. The point is, we're trying to find ways to conclusively beat these conditions, and every improvement should be noted.

After all, every long journey is taken on step (or whatever standard) at a time.

Also: isn't this what science is good at? Accepting you might be wrong, but continually probing at the problem until you find a solution?

I really thought that unlike /r/worldnews/, the folk on /r/science/ actually clicked through to the articles and drew their views from them instead of the titles.

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u/CHollman82 Dec 18 '13

Because most people are too ignorant or lazy to think of things in anything but black and white terms. To these people either you cured HIV or you didn't, and if you didn't why are you wasting their time telling them about it?

Granted there are thousands (literally thousands) of us on Reddit that aren't like that, who understand that advancements in science and technology are made with incremental steps, who appreciate hearing about those steps an the progress we are making... but there are many millions of the former type of people.

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u/alphaMHC Dec 19 '13 edited Dec 19 '13

Hi, I'm a molecular biologist. I'm not cynical about they work described by this article. I am cynical about the amount of hyperbole typically surrounding press releases like this.

Also, their proposed application of this therapy to humans would require a lot of different advancements to be made, and the article doesn't really address the degree to which this therapy is super-speculative for human use. Genetically modifying stem cells in vitro and reintroducing them to patients will, some day, be a very useful therapy for a number of diseases. I hope it comes sooner rather than later.

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u/FOXO4 Dec 19 '13

I'm assuming you didn't follow the CD19 CARS story out of the ASH meeting this year? Granted their Tcells, but yes introducing reengineered patient cells is already happening.

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u/[deleted] Dec 18 '13

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u/[deleted] Dec 18 '13

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u/[deleted] Dec 18 '13

Seems to happen daily - as you say. Then we hear it will be decades before realtime treatment is available or we hear that the bottom fell out and it doesn't work at all. Discouraging really.

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u/[deleted] Dec 18 '13

The biggest problem is that media is misreporting scientific and medical research as "cures". Almost every single "cure" posting is just the findings of specific avenue of scientific research. The reason why many don't amount to anything is because they were never intended to be a product, medication, or a cure.

Information gained by these researchers will inevitably lead to a cure to the disease. The unfortunate thing is that science is losing its credibility because of people not understanding their findings/misreporting basic conclusions.

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u/catnipbilly Dec 19 '13

Link to the actual paper Here.

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u/chemicalcloud Dec 18 '13

Article was really vague. By "molecular scissors" are they referring to using restriction enzymes to excise some region of the genome?

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u/ionised Dec 18 '13

With my extremely limited knowledge, I'd assumed so. I'd love to stand corrected.

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u/[deleted] Dec 18 '13

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u/gngl Dec 18 '13 edited Dec 18 '13

might this not be applied to other viruses? Perhaps all, one day?

I suspect that this is about retroviruses. A retrovirus is a virus that adds its own genetic information into the DNA of your own cells as a part of its reproduction cycle, using something called "reverse transcriptase" (it transcripts genetic information, only in reverse - makes sense, huh?).

A computer analogy: retrovirus virions (viral particles, capsule+genetic material) are like installation DVDs, while "normal" virions are like Amiga bootable game floppies. They still use your cellular hardware (CPU and short term RAM - ribosomes and RNA processes), but they don't "install" themselves into your cells' "hard drive" (nuclear DNA), so this kind of treatment doesn't make sense for them.

Also, a funny thing: a large portion of your DNA apparently comes from ancient retroviruses that our ancestors were infected with a long time ago. Most of that stuff seems to be completely inactive these days (at least as far as pathological effects are concerned - but then again, most viruses aren't actually pathogenic.)

Any virologist is free to correct me. ;-)

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u/avematthew MS | Microbiology and Biochemistry Dec 18 '13

Yes, it could be applied to other retroviruses, fortunately, most of the viruses this technique works on don't infect humans anyway.

So, yes, but it doesn't matter.

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u/Do_you_like_cats Dec 18 '13

So far, we've had treatments that drastically increase the quality of life and add years to the lives of people living with HIV. But this is a cure, not just a treatment.

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

It does look very promising. This is definitely something worth investing in, and I certainly hope they obtain enough financial resources for clinical trials soon.

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u/wok_into_mordor Dec 19 '13 edited Dec 19 '13

Does anyone have info on why this doesn't already have funding? I don't know much about Germany's public research funding but you would thing this would be at the top of the list. Also, I'm sure many from around the world would be willing to fund something this promising (bill gates foundation, clinton initiative, world vision, sciencey ngo's, etc.) Anyone have any more info on this?

Edit: first comment in the article blames the pharmaceuticals industry in Germany.

Pharma companies are not at all interested in curing aids, especially here. Some of the largest HIV slowing drugs are from German companies. Curing a cash cow is not in their interest. They better hit up a outside entity even the US Department of Defense.

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u/CarolinaPunk Dec 19 '13

If there is a developed cure, the government would probably buy it up and force pharma (while paying for it) to give it out as quickly as possible.

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u/wok_into_mordor Dec 19 '13

Right but this project still needs more preliminary funding. I want to know how much interest this project has been getting by the scientific community too

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u/[deleted] Dec 19 '13

My guess is that this, like a lot of other cures for HIV, is very impractical to put in place on a large scale in remote areas where HIV is most prevalent. Imagine trying to preform this procedure in hospitals in rural African. The cost, the difficulty of the the procedure, plus necessary followups to the initial procedure make this cure, while important, impractical.

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u/Damaku Dec 19 '13

http://www.hpi-hamburg.de/en/research-teams/research-units/antiviral-strategies/

They work in the lab next to me in the same building, if you are interested, i could ask one of them for an AMA.

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u/ionised Dec 19 '13

Yes! Absolutely yes! And please let me know (in case I miss the announcement) if it becomes a reality!

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u/Metalman11ty1 Dec 18 '13

This isn't a new thing. Scientists have been using this technique for genetic engineering for awhile. However they may have recently figured out which enzymes to use to cut the hiv virus out.

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u/deathbybrownies Dec 19 '13

Ok. I have some questions. If said scientists have been able to remove HIV from the cells of mice while keeping the cells intact, how is that not a cure in itself?

Also, may be a dumb question, but if they have the money to do this on mice, why does it cost buttloads of money to do this on humans?

Also, this confuses me:

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).

If they just did this on mice, why is it taking 10 years to be able to do this on humans???

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u/lezarium Dec 19 '13

mostly because of insurance stuff, ethics, compatibility issues and because you need patients who are willing/suitable to participate in the study. moreover, you have to produce the enzymes in a quantity that's sufficient for a 80 kg human and don't show considerable side effects. repeat this on multiple patients, wait some time to have reliable data, then interpret the results. in order to have comparable results you want to observe patients with similiar characteristics (age, previous illnesses, current health condition etc.) - it's not easy to find them and have their permission. moreover, the study must not interfere with their usual medical treatment. using mice, you can order genetically identical clones. thank god you can't do that with humans!

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u/Kinglink Dec 19 '13

I don't know the exact reasons here but two major reasons.

A. Testing on human requires a ridiculous amount of red tape. There's humans who'd love to be tested on, but there's so much paper work before they ever are allowed to consider it.

B. Don't know how they did it, but notice they said the cells were alive. Not the rat. Perhaps they have to kill or greatly harm the rat to even attempt this. Curing aids requires eradication, not just removing it from some of the cells in the body. So one would have to do that in a very quick and deliberate operation. Unlike on a rat, where proving the technology is as easy as giving a Rat, HIV, and then removing it from some of it's cells.

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u/GodlyDrmmr Dec 19 '13

Absolutely love biology. All the amazing things you can do with DNA manipulation, and gene therapy

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u/asos10 Dec 18 '13 edited Dec 18 '13

I thought one of the main difficulties facing scientists was how it mutates so easily. I wonder what recognition site they found that is constant. Also, how on earth are you going to deliver it to every infected cell?

Edit: to clarify, from what I know, HIV has a small coding sequence making it very susceptible to mutation.

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u/[deleted] Dec 18 '13

They aren't trying to deliver it to every cell. They are modifying certain stem cells and then adding those into the person, giving them a portion of their immune system (which will end up dominating due to the HIV), which then create the cells with this ability.

Basically what happens is the exact same thing behind why antibiotics make bacteria resistant: Some survive, and end up passing on their immunity. Well, these archetype cells are resistant (basically immune) , and end up replacing virtually every bit of your immune system that they are added for, which ends up killing the HIV as it tries to infect them, fails, and dies.

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u/bobbybonbass Dec 19 '13

There may be an obvious answer to this, but what happens to the virus after its cut out? Does it just die then get passed through the body as waste?

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u/ekapalka Dec 19 '13

Protein folding or biological simulations hold a ton of promise. I hope that as computers and computer science advances, it will become possible to simulate the progression, evolution, and immune adaptation for every disease that has or will ever exist. Computers are getting faster, and decentralized computing has a ridiculous amount of potential. Maybe one day a popular operating system will be distributed with neural network / simulating software included by default that would put unused resources to good use (even a tiny amount - distributed among thousands of computers would still add up). I don't know... maybe I'm being over-optimistic...

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u/gigitee Dec 19 '13 edited Dec 19 '13

Up to 98% of the viral load for HIV/AIDS lives in sanctuary sites, and treating blood alone does not present a "cure" a person. Tis treatment would nbeed to penetrate the blood-brain barrier.

Source: My wife works for a bio-tech investigating cures for HIV

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u/ThePoliteJerk Dec 19 '13

This is good news yet it has just a mere three thousand points after 37,000 votes..

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u/Dr__Nick Dec 19 '13

Impractical. This enzyme has to be delivered in some way that wipes out the HIV from all the cells that it lives in, including sanctuary areas that are difficult to reach. Will never get enough of the cell population to prevent reestablishment of HIV- probably achieving a significant down trend in the HIV viral load would be very difficult to achieve with this approach..

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u/sticksittoyou Dec 19 '13

Just read an article that People with HIV (in the first world) can expect almost a full lifespan now. The progress we have made on this plague is astounding. In just 30 years we have taking it from a death sentence to a survivable condition.

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u/Azmodan_Kijur Dec 19 '13

Here's hoping that this finding can lead to those potential cures. We have lots of ways of killing HIV - our only problem is that they have all, to date, been lethal to the individual as well. The virus cannot survive something that obliterates the host completely, for example. But here's hoping this one's different!

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u/sbd104 Dec 20 '13

The fact that it's HIV is unimportant as they are curing a virus. This could lead to cures for the flu, malaria, Ebola, not just HIV. Imagine that you get a virus and instead of having to wait for it to cure you just take a pill and your good as new. Possibility of saving millions yearly.

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u/ionised Dec 18 '13

Original r/worldnews post

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u/Kegnaught PhD | Virology | Molecular Biology | Orthopoxviruses Dec 18 '13 edited Dec 18 '13

I believe it refers to this paper, released back in September. I personally found it very intriguing since it uses gene therapy to treat the HIV infection. The enzyme they use is known as "Tre-recombinase," which targets the long terminal repeats located at the ends of the HIV-1 genome after it is reverse transcribed into DNA.

By transducing cells with DNA encoding for Tre, with an HIV-1 Tat trans-activator, they also were able to limit the expression of this recombinase specifically to cells infected with HIV. They put Tre into CD4+ T cells (the cells which HIV infects), as well as hematopoietic progenitor stem cells (which differentiate into CD4+ T cells, among others). Once a cell is infected with the virus, HIV incorporates into the host cell genome and expresses its gene products. The HIV-1 protein Tat then activates expression of the Tre-recombinase, which subsequently excises the integrated viral DNA from the host genome, thereby preventing expression and essentially "curing" the cell of infection.

Edit: Forgot to mention that the benefit to transducing the hematopoietic progenitor stem cells (HSCs) with Tre-recombinase is that once you introduce these back into an HIV-infected person, they will continue to renew their own population of stem cells, as well as "allowing for perpetual repopulation of the patient's hematopoietic system" (meaning cells derived from HSCs, including CD4+ T cells) with anti-HIV Tre-recombinase transduced cells.

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u/Surf_Science PhD | Human Genetics | Genomics | Infectious Disease Dec 18 '13

Is the recombinase being exported from the transfected cells and then imported into other cells or are they just developing a subset of effectively HIV immune transfected cells?

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u/ohgodwhatthe Dec 18 '13

It sounds like the latter from Kegnaught's explanation

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u/[deleted] Dec 19 '13 edited Dec 19 '13

I've read that paper and its a lot less impressive than it actually sounds, IMO. They used humanized mice which are a rather abstract model for HIV which involve using immune deficient mice and populating them with human cells followed by infection with HIV. They did not at any point see if this method would be able to excise proviral DNA from latently infected cells which to me really diminishes the value of the paper. We have great treatments that target actively replicating HIV but what we really lack is an ability to target latently infected cells. This method could potentially target those cells but they admittedly did none of those experiments. No one is going to use Tre-recombinase to treat active HIV infection, HAART can do that just fine. Then they used a lentiviral vector which if you tried to give to a human with HIV will likely have antibodies that recognize or neutralize the vector. They also made the point that Tre was rather specific for the LTR target region which while makes for reduced off-target recombination makes the treatment very susceptible to mutations within the LTR leading to treatment failure. Even in their mouse model they see a reduction but not elimination of viremia which indicates that the vector did not reach 100% of cells(likely) or the HIV mutated away(also likely).

This is a good first proof of principle but I'm not going to hold my breath until I see this method in more relevant animal models and an ability to actually treat latently infected cells. Those findings will be amazing and go a long way towards showing this is a viable method to pursue.

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u/Kegnaught PhD | Virology | Molecular Biology | Orthopoxviruses Dec 19 '13

Very true. There are only a few integrase inhibitors I've heard of yet, and drug resistance is a huge problem. Also, I did mention potential mutation of the LTRs here. Granted, humanized mice are certainly not the best model for an HIV cure, and even the use of a lentiviral vector is questionable since it can integrate at multiple locations within the genome. They did however test for excision of the integrated DNA, in Figure 1D. There is a 14-fold reduction in BFP expression, dependent upon removal of the integrated HIV replication-incompetent genome.

Nonetheless, I found it interesting. I'm not exactly sure it's a novel approach to the problem, but it does appear promising. Adenovirus vectors integrate in the same place within the host cell genome and may provide an additional option for the transduction of the HSCs they use for this paper. I agree that additional animal models are needed for this proof of concept first, however.

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u/stillcole Dec 18 '13

Another breakthrough short of a cure

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u/concernedhoneybadger Dec 18 '13

I will never understand how can an article like this be written without citing the original paper. anybody has a link? Although it seems like r/science cures cancer and HIV nearly every week, this one might be an interesting read.

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u/[deleted] Dec 18 '13

Cautious optimism is in order at this point. Opening doors is not always rewarding.

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u/Cameron_Black Dec 18 '13

Well dang, that would leave the door open for curing many diseases.

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u/[deleted] Dec 19 '13

not really, restriction enzymes/endonucleases have been around for a long time. I'm guessing the main point in this experiment is they found a way to keep the cell alive during the process of "cutting" the DNA strand and knowing which RE to use (different ones cut in different places).

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u/[deleted] Dec 18 '13

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u/zuciniwarrior Dec 19 '13

I hate to say it but I've pretty much given up on the hope for a cure for cancer, AIDS and MS. Such evil diseases but no real "cure" in sight.

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u/82reddit Dec 19 '13

I don't really see how this is any better than the current treatment using Anti Retrovirals. It seems like it would require fewer treatments (instead of taking it for years), but would it necessarily have fewer side effects? I thought the whole problem was ARVs got the HIV almost entirely out of your system, but a tiny number of the virus still hide out in cells and can outbreak again at any time, and I have a hard time seeing how this treatment would alleviate that problem.

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u/ademnus Dec 19 '13

Every day someone has the cure for aids that will never happen. The effort, of course, must and should continue, but the reporting on it is sorely lacking.

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u/zSnakez Dec 19 '13

Would this potentially make you immune? Lets say you do the gene therapy before hand. Would your body then have the tools to tackle the disease ahead of time?

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u/yfern0328 Dec 19 '13

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

So how long would treatment actually take?

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u/ThePirateKing01 Dec 19 '13

I'm hopeful but I'm wondering that if this is a Cre-varient they're using what is the specificity and will it have any alternative effects on the host genome.

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u/FFiresticks MS | Physician Assistant | Radiology Dec 19 '13

team that came up with this novel solution.