Im sure you all remember the guy I wrote about a while back, who had HIV-1 and leukemia. While that is actually pretty common, what wasnt common was his treatment– a bone marrow transplant from a match who happened to lack the CCR5 gene, thus lacked one of the co-receptors HIV-1 needs to infect cells. This was a death-blow to the HIV-1 in this guys system. The virus in him simply has no (or very few) place else to go, so it burned out.

But this is simply a non-viable idea for ‘curing HIV/AIDS’ for basically everyone else on the planet. Financial barriers, technological barriers, immunological/genetic barriers (not enough people who are delta-CCR5, certainly not enough have the genetic diversity to be an appropriate match for everyone with HIV-1).

A new idea has come up that doesnt help with the first two problems (but technology does get cheaper over time), but it helps with the last problem– What if we could make any bone marrow donor delta-CCR5?

Generation of human induced pluripotent stem cells bearing an anti-HIV transgene by a lentiviral vector carrying an internal murine leukemia virus promoter

How this would theoretically work:

1. Find an appropriate genetic bone marrow match for the HIV-1+ patient, OR, get bone marrow from the patient him/herself (though some say bone marrow is infectable with HIV-1, so this might not be possible)
2. Treat the bone marrow with a lentivirus that contains an MLV promoter for an anti-CCR5 gene
3. Bone marrow transplant to HIV-1+ patient
4. The bone marrow will generate new immune cells.
5. The new immune cells are genetically modified by the viral vector to express the anti-sense CCR5 RNA, which will bind to the normal CCR5 mRNA. This double-stranded RNA PISSES OFF the cell, so it destroys it. Thus CCR5 mRNA is never translated into CCR5 proteins. The person is functionally, if not genetically, deltaCCR5.
6. PROFIT!!!

Of course, things really arent that straight forward. Bone marrow transplants arent a casual deal– over 10% of the people who get them die from complications. You cannot get one unless its life-or-death, and if youve got HIV-1 thats under control with meds, you arent gonna get one– Just people with HIV-1 AND leukemia/lymphoma.

And then theres the gene therapy side of it. MLV has a great promoter we can pirate to get the anti-CCR5 RNA made, and it knows to keep its mouth shut in the pluripotent state, so their wayward gene expression doesnt screw up the normal development of various cell types… but it causes… leukemia and lymphomas (except when it doesnt). But lentiviral vectors have some advantages over MLV. So they cut/pasted a lentivirus with the MLV promoter with the anti-CCR5 message (previous post on cutting/pasting viruses together to make better gene therapy vectors).

And, everything in this paper is in culture dishes. Not people, yet. What if the stem cells (or their progeny) just quit making the anti-CCR5 message? Does that happen in one year in people? One month? Ten years? We dunno. We dont really know what controls latency in regular retroviruses yet, certainly not ones we are screwing around with. Nothing would be as disappointing as going through this ordeal, surviving it, thinking youre ‘cured’, and things go to shit again in a few months/years.

But as far as tissue culture work goes, this is nice. And even if we cant ultimately use it for HIV-1, we might be able to use the technology these folks are working on for any number of diseases.

Comments

  1. #1 Ron Neufeld
    July 21, 2010

    That is simply brilliant. Made my day.

  2. #2 Tatarize
    July 21, 2010

    I could see a time when taking skin cells, genetically tweaking them, dedifferentiating them and turning them into bone marrow, them and injecting them back into an individual becomes cheap and feasible and would give individuals a reserve of protected cells. There’s something about this that just rings of failure. And if such solutions end up advancing to be actual solutions and economically viable solutions at that, then it rings of failure.

    I know that there’s no limit of the number of amazing fun things discovered about the human immune system and about HIV and vaccine technology (even if they didn’t work for HIV they are some fantastic ideas there in the attempt), etc etc etc. And I know that understanding HIV is what makes such genetic approaches even feasible, but seriously something about the thought that this might work eventually just tastes like a Pyrrhic victory (even if you did a lot of really great stuff and learned a lot along the way). It’s like HIV research would fail and stem cell research ends up with the winning kick. It would be like if cancer research ends up going nowhere but somebody makes nanobots that can go into the body and identify and irradiate cancer cells. If tiny robots or genetic engineering solve the problem you tried to solve, it’s a bit like you failed.

  3. #3 Stephen Wells
    July 22, 2010

    @2: You’re worried that the successful development of treatments that defeat HIV will represent a failure for HIV research?

    Strange.

  4. #4 Paul Browne
    July 22, 2010

    There was a paper in Science Translational Medicine last month which did in fact report the stable expression of anti-HIV transgenes (a lentivirus based vector driving expression of tat/rev short hairpin RNA, TAR decoy, and CCR5 ribozyme) in hematopoietic progenitor cells transplanted into four patients.

    http://www.ncbi.nlm.nih.gov/pubmed/20555022

    This shit is real!

    Interestingly in addition to in vitro and clinical studies this work has used SCID-hu mice which lack an immune system of their own but have human fetal thymus and liver cells injected that give rise to human lymphocytes. So you essentially have a mouse with a human immune system that is proving a useful model for HIV research

    http://www.ncbi.nlm.nih.gov/pubmed/12842429
    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0000655;jsessionid=3E500200246F556907EC0688B2A31823.ambra02

  5. #5 gf1
    July 22, 2010

    I’d assumed #2 was joking… maybe not?

  6. #6 John C. Welch
    July 22, 2010

    #2:

    “If you don’t care who gets the credit, there’s no limit to the good you can do.”

    George Marshall

  7. #7 Dave
    July 22, 2010

    OK, so a couple of questions:

    1 – Does this mean delta-CCR5 people are immune to HIV? (I recall reading your post about the bone-marrow transplant, but didnt think it through at the time.)

    2 – Why would it matter if the bone-marrow is infected with HIV? Wouldnt treating with the lentivirus kill off the HIV since the CCR5 is then repressed?

    3 – Whats the down side to being delta-CCR5?

  8. #8 Stephen Wells
    July 22, 2010

    Wiki tells me that being homozygous for delta-CCR5 does confer HIV infection resistance (Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, et al. (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: 722–725).

  9. #9 Orakio
    July 22, 2010

    Dave, as best as I understand it, though I may be wrong:

    1: Strongly resistant, but not perfectly immune. Standard CCR5 provides the ‘best’ route of entry – For HIV, it is the difference between driving up the highway and the Battan Death March.

    2: If the HIV is in the marrow, it matters because the therapy works via a form of ‘starvation’ for the invading virus. A cell that bears the HIV DNA at replication will not need an invasion route – it’s already there, after all.

    3: Resistance to certain other viruses is weakened. Would you rather have AIDS, or West Nile?

  10. #10 ERV
    July 22, 2010

    (lol, Orakio beat me to the punch as I was typing this)

    Dave–

    1– Transmission of HIV-1 from one person to another is associated with the co-receptor the virus uses: CCR5 are generally transmitted, while CXCR4 tropic viruses generally are not. So people homozygous delta-CCR5 are resistant to acquiring HIV-1 in the first place. *Resistant* to infection, not uninfectable/immune/etc. CXCR4-tropic HIV-1 can infect cells that lack CCR5 just fine, if given the opportunity.

    2– If the bone marrow isnt totally clean, you run the risk of having a cell in the mix that can make CXCR4-tropic viruses. And CXCR4 viruses are more pathogenic. The patient would be royally screwed.

    3– People without CCR5 are more susceptible to West Nile Virus infection. Thats the only down-side we have found so far :)

  11. #11 Dave
    July 22, 2010

    OK, Im a bit out of my depth here, so dont screw me if I mess up the U of Google education Im taking on this, But . . .

    It appears from wikipedia (article on CCR5) that the transplant dude had HIV-X4 infected cells at the time of the transplant and yet even those dissapeared after the transplant. According to the article, apparently cells expressing CCR5 also lack CXCR4. (Apparently the CCR5-delta protien not only doesnt act as a receptor but “down regulates” CXCR4.)

    Presumably then the supression of CCR4 via the lentivirus would still have CXCR4 since the lack of CCR4 is not the same as the presence of the CCR4-delta. Or has GoogleU failed me here? Also, it the above paragraph is true, then how do the CCR5-delta people get infected? (One of the articles I read said that some homozygous CCR4-delta people have been infected but the method of infection was unknown.)

    It would appear that there are also drugs (mostly experimental) to bind to CCR4, yet as I read the wiki articles on them, they seem only to decrease the viral load, not eliminate it. Is that because such a drug wouldnt get all CCR4 while this viral/transplant approach would? Or is there some other issue?

  12. #12 Orakio
    July 22, 2010

    Dave,

    This article would appear to indicate that the down regulation of CXCR4 isn’t complete enough, and still exists in homozygous deltaCCR5 individuals and that further, other pathways exist through CCR2 and 3 – These are how HIV can get into the nervous system, apparently.

    As for the drugs, if Google U hasn’t failed me, I suspect that you have a handful of problems. The first, of course, is the halflife of the drug – if it only binds for x time, and is only in the blood stream for so long, a given cell wil be vulnerable to infection a certain period of time before the drug rebinds with the next dose. The second is that yes, it would be difficult to guarantee total coverage, depending on at what point side effects start becoming lethal. The third is that some forms of HIV have a stronger chemical bond to the CCR5 receptor than the antagonist does. Therefore, they can kind of ‘muscle off’ the drug and get in anyway.

  13. #13 scramton
    July 29, 2010

    I may be too late to get in on the comments,I’m a late bloomer on sciblogs, I think this introduction of human immune system in mice is interesting, where besides wikipedia and pubmed can i research this? I teach Physics so I’m not up on these journals.

  14. #14 sue
    August 1, 2010

    what if they get the bone marrow from the HIV+ person, use that Tre Recombinase enzyme to remove all the HIV, then genetically alter the cells to be CCR5 deficient, and then put them back in the patient?
    sue

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