h a l f b a k e r y"Look on my works, ye Mighty, and despair!"
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I was just watching a program on PBS (called "Secrets of the Dead") where it was proposed that people with two copies of a genetic variation called "delta 32" were immune to the HIV virus. Those with one copy (heterozygous) have a marked resistance.
To me this suggests a possible treatment for
the HIV virus: umbilical cord blood transfusion from HIV immune cord blood.
Suppose couples that were both homozygous (two copies each) for this gene (delta 32) donated the cord blood of their newborn children (who in turn would automatically also be homozygous in this gene).
If this cord blood was transfused to someone who is HIV positive and a close tissue match (this point is crucial since someone who is HIV positive should never go on immune suppressing drugs, for obvious reasons), the stem cells would establish themselves and produce (among other things) T-Cells that were immune to the HIV virus.
To make this a possiblity (if initial trials verified a positive effect):
(1) A national database of tissue types of HIV positive individuals would need to be compiled.
(2) Free voluntary testing for the delta 32 gene (or if it turns out to be other genetic factors, those genes) be offered.
(3) A national campaign with public service announcements and celebrity/activitist endorsements as well as rallies and events to promote testing for the delta 32 gene and cord blood donation.
(4) Lots and lots of federal and private monies to make the other points possible.
I think this could really work. My brief google search didn't come up with anyone investigating along these lines, but I wouldn't be surprised if this was being looked at.
Patent Listing From StemCyte
http://www.wipo.int...o.jsp?wo=2003045335
A patent listing for this idea. [talldave, Jun 20 2008]
StemCyte Press Release
http://www.stemcyte...about/pr022108.html
A StemCyte Press Release discussing various stem cell treatments. [talldave, Jun 20 2008]
Transplant from HIV-resistant donor to cure HIV
http://www.time.com...599,1858843,00.html
this idea, done. [bungston, Nov 13 2008]
Cured
http://health.usnew...s-urge-caution.html
Works! [bungston, Dec 15 2010]
[link]
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Fine idea, [talldave]. There are a few details in your proposal which are a little off, but the principle is rock solid, and a nifty inversion of the usual rationale for stem cell transplants. Such transplants are often done to replace the cells of a child born with cells that lack some normal function - either a subset of the immune system is missing (like the bubble boys), or the kids lack a metabolic enzyme (like Hurler's syndrome) and so metabolic trash builds up - the transplanted blood cells possess the enzyme and so can break down the metabolic trash. |
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The cool inversion is that it is normal, common variant which is deficient (it does not resist HIV) and this can be corrected by introduction of a special mutant version. The immunosuppression thing would not be that big an issue, I don't think. The folks who would sign on for the first trials of this would be desperate folks in pretty advanced stages - either the stem cells reconstitute and the HIV can't get reestablished, or the patient dies of HIV or graft failure or graft vs host or infection. |
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I like it. It is straightforward. If it worked the mutant folks would get rich. Their stem cells would be in great demand. Adult stem cells could be used as well as infant cord blood, and there is more of the former. |
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The issue with immune suppressors is that a person with an autoimmune disease could be have their immune system completely compromised by the introduction of immune suppressing drugs. |
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I've read that cord blood transplants are more tolerant of mismatches of tissue types than bone marrow transplants, but a good match is still key. |
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Intriguing idea. A couple important foreseeable issues: |
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1) Is the HIV-resistance conferred by this allele confined to cells which carry the allele, or does delta-32 encode some serum-secreted factor &c. that may confer resistance to other same-tissue cells? Is the key expression in a precursor of T-cells at all, or rather in some other associated cell lineage(s)? |
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If resistance is confined to delta-32-bearing cells (T or otherwise), we'd have to hope that such a graft would suffice to re-establish a full 'normal' (or better) T-cell complement -- else the patient would stay at least a bit sick. Better than full-blown AIDS, tho. |
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If the latter, you may be on to something bigger. |
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2) Even beyond drug issues, allograft risks some longterm complications (not least HIV transmission itself, tho that's not a big problem for your proposal per se) -- -especially- immune-related ones -- due to such common genetic differences as sex (XX vs. XY). How comfy would we be encouraging newly resistant allograft recipients to engage in epidemiologically risky behavior at all? |
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[n-pearson] brings up the point of complete HIV eradication in the allograft recipient. I bet it would not happen. Supposedly other cells in the body (kidney, Langerhans cells) can harbor HIV, and the virus could cause trouble there. |
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As regards problems related to allografts - no doubt. But desperate measures require desperate solutions, which is why allografting was developed in the first place. I think it is likely that there are not many HIV patients, who are transplant candidates by virtue of their general good health, but who have uncontrolled HIV with current state of the art treatments, who are genetic matches with a wiling delta-32 mutant donor. |
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There has been progress in genetically engineering T cells before transplant. Unfortunately some of those french kids got cancer because the inserted genes disrupted a tumor suppressor. I am not sure the technology exists to knock out a specific gene, but if it did, any suitable stem cell donor could give cells, which would then by "HIV-proofed" in vitro, then transplanted. The cancer risk is a big deal for kids with metabolic diseases - probable less of a big deal for someone who is facing an imminently lethal problem anyway. |
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My understanding of the resistance confered by the delta 32 gene (and I am not an expert by any stretch of the imagination, just a fan of biology) has to do with the gene eliminating a surface feature on T-Cells that HIV uses to enter those cells. |
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HIV's lethality lies primarily in its ability to knock down the immune system, so if this is eliminated, even if other tissues are infected, the immune system will still be active to keep the virus in check. |
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HI my name is George and I am an undergrad at Penn state. One of my assignments was on the HIV resistance genes caused by the truncated receptors. However, I am unabe to come up with answers my professors wants answered. I would aprreciate any help?
1.) would a person who is resitant to HIV be tested for infection just like an individual whose M-cells and T-cells have been infected by the virus?
(Methods i have seen so far are ELISA, rapid tests and simple tests)
2.)Can bone marrow transports be used to rid of HIV completely by eliminating an individuals stem cells(assuming the body accepts the bone marrow tranplant)?
3.) Are there any other methods wher scientists can detect differences in alleles other than the method used in the research for AIDS Resistance genes? |
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George - here is some help.
1: What exactly do the AIDS tests look at? For each of these things, determine how the thing would differ between a normal and an aids-infected person. Then you can determine how useful each test would be for a resistant person.
2: The question is whether the virus can be found in the body outside the stem cells. If it can, eliminating stem cells would leave some virus. If it cannot, eliminating stem cells would work.
3: No idea what you are talking about here. |
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I found this web site because i just tought of a similiar idea - I think that a bone marrow transpalnatation from a homozigous delta 32 (deletion size 32 at the gene for the CCR5 chemokin receptor) donor will do, instead of a cord blood stem cell. this can maybe come as a "vaccine" but will not heal patiants, as HIV starts by entering monocytes which have a CCR5 receptor, but then mutates and start attacking T helper cels with CXCR4 receptor which the delta 32 patiants are not immune to. |
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It has got to heal them to make it worthwhile. Allogeneic marrow transplant as a vaccine to prevent a disease - talk about a solution worse than the problem! It is too harsh and dangerous to be used in this context. But to replenish a body with a store of resistant T-cells; that might make it worthwhile. |
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Welcome, [erez]. I look forward to seeing some of your ideas. Hopefully spellchecked. |
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I found some links that either I didn't see or weren't there when I first posted this idea. |
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Interestingly, the search date for the patent is listed as a month before I posted this. |
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Apparently, the idea may be very baked. |
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Hello talldave,
I liked your idea a lot as much as people doing it a reality. I would like to get in touch with you if possible, also to be sure to unblock any possibly patents that were claimed on the subject. |
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I think the idea is a no go. If it doesn't work easily in cases of immune suppression where host stem cells are reintroduced then what are the odds of a good T-cell yeild for non-host (incompatible) T-cells? You would need to completely disable the immune system and there simply isn't any reason to believe that this would protect a patient who already had a substantial viral load. The patient would have to have immunologic suppression while suffering a disease that causes critically low levels of immune function in the hope that a foreign immune system would completely replace their own, AND be able at that point to fight off a virulent viral load for which it is only resistant; that's a really long shot. |
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Things have changed since 2010. The people to try this on are the compliant folks who have successfully fought their HIV but who are developing resistance. This selects for the sort of people best able to also deal with side effects of transplant. Second and third line treatments do work for HIV as for cancer, and transplant in the context of minimal residual disease (also as with cancer) would minimize the chance of being blindsided by HIV while new graft came up to speed. Also recipients could continue their HIV meds with the new graft and so keep HIV on the ropes while it took. |
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Finally: the fallback plan. Autologous transplants are routinely done in the context of high dose chemo vs lymphoma for people with or without HIV. The recipient of the allo could bank his own cells. If the new graft failed or caused uncontrolled graft-vs-host, he could ablate it and get his own cells back. |
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how is this not the perfect way to culture a new strain that can hit the genetically resistant natural population? |
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[WcW] According to that reasoning, every new antibiotic
that's come along since Alexander Fleming ought really to
have been locked in a safe and never used. And of course,
all the antiretrovirals currently used to treat HIV as well. |
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It's all about weighing risk vs. benefit. How many naturally
immune people will die as a result of this? And how many
others will live, because of it? |
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The ID guys think about this stuff *all the time* and design
policies that are supposed to optimize the balance
between risk(to the population) vs. benefit(to the
individual patient). But surely you don't think a patient
should be
allowed to die because of a statistical risk to the general
population from a possible future resistant organism. |
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/is this not the perfect way to culture a new/ |
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it is not at all the perfect way but a very circuitous and Rube Goldbergish way to accomplish that end. WcW I am sure you could come up with 3 great ways to culture a new strain much more simply and easily than this approach. |
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It's hard to get a strong novel mutation unless you can maintain a high viral load, somewhat easier if other viruses are also thriving. then give a sub-effective but conventional immune response, (best if the antigen is for a protein that is indicative but not important) then wait. Shouldn't take very long, possibly as few as 40 host cycles, certainly fewer than 400 (obviously this only applies to to the scenario described). I believe that M. Creighton had a novel based on a similar premise. |
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AIDS patients are awesome sites for culturing virulent disease. |
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