HIV-resistant donor confers resistance to recipient...?

[Trieste]

Don't have the time to look up the actual study itself, but a friend just tossed this to me.

http://www.advocate.com/News/Daily_News/2010/04/02/Stem_Cell_Transplant_Patient_Free_of_HIV/

Oh god, I hope it's a case of causation and not merely correlation.

[DarklingAlice]

It is! It is actually quite an amazing process. I wish I had time to discuss it at length now, but as I have to leave in just moments I will fall back on that most base of rhetorical tools: quoting myself on the subject.

An intriguing procedure was carried out by a group of doctors from Charite Universitatsmedizin Berlin and the Robert Koch Institute, the details of which were published in the February 2009 New England Journal of Medicine. The patient was a 40 year old, white male who was HIV+, heterozygous for the CCR5delta32 mutation, and afflicted with acute myeloid leukemia. As chemotherapy interfered with his HAART treatment, a CD34 stem cell transplant was performed. A list of HLA matching donors was found, and these potential donors were screened for CCR5delta32 homozygosity. The patient received an initial load of stem cells and then, after a relapse, underwent total body radiation and received a second load. HAART was discontinued after the first treatment. 20 months after discontinuation of HAART there has been no rise in viral proteins. Further PCR assays reveal that the patient is now homozygous for the CCR5delta32 mutation

And here are a number of references on this particular case and the more general topic of inhibiting HIV via CCR5:

Hutter, G., Nowak, D., Mossner, M., Ganepola, S., Musig, A., Allers, K., Schneider, T., Hofmann, J., Kucherer, C., Blau, O., Blau, I., Hofmann, W., and Thiel, E., (2009). "Long-Term Control of HZIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation." New England Journal of Medicine 360, 692-698

Shearer, G., Clerici, M., (1996). "Protective immunity against HIV infection: has nature done the  experiment for us?" Immunology Today 17, 21-24

Lui, R., Paxton, W., Choe, S., Ceradini, D., Martin, S., Horuk, R., MacDonald, M., Stuhlmann, H., Koup, R., and Landau, N., (1996). "Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection." Cell 86, 367-377

Verani, A., Lusso, P., (2002). "Chemokines as natural HIV antagonists." Current Molecular Medicine 2, 691-702.



It is notable that this is not without its own risks. In fact there was a recent review article on that topic, I will try to dig up the reference a little later.

[Trieste]

Duh, I read the release as Feb 2010 and thought it was a year more recent than it was. I'll look in my nooks here, too.

Thanks, Alice! You are, as usual, tehroxxor!

[Oniya]

I wonder if the patient will eventually show a decrease in viral proteins... *crosses fingers and hopes*

[DarklingAlice]

And <a href=http://www.journals.uchicago.edu/doi/full/10.1086/649427>here</a> is the editorial from the Journal of Infectious Disease (volume 201; issue 2)

Its a general look at the various natural mutations that confer immunity to one disease while making you vulnerable to another. In the specific case of CCR5delta32 the trade-off is worse symptoms from WNV. That case seems pretty clear cut given the relative severity of HIV versus WNV. Other cases are a little more interesting, for instance the choice between malaria or sickle cell or malaria and susceptibility to HIV.

Thanks, Alice! You are, as usual, tehroxxor!

Hee, thanks! It helps when you ask about things on the list of potential topics for my master's thesis.

I wonder if the patient will eventually show a decrease in viral proteins... *crosses fingers and hopes*

At least according to the article Trieste linked he is now HIV free.

I do wonder a bit though, at the time I wrote on the subject there was a small level of CXCR4 tropic HIV in the patient's bloodstream. It is interesting that that has not risen to prominence in the intervening period. Also I think CCR5 was still expressed in his macrophages, and they were worried about the possibility of infection there. So it makes sense that his T-cells are free of CCR5 tropic HIV, but it would be interesting to hear whether the CXCR4 tropic is gone, and why.

It is unfortunate that this procedure is A) too expensive, B) dangerous, and C) some will say unethical (although I think they are wrong on that point). Basically it can never be used on the large scale it would need to be to make a sever impact in the HIV epidemic. However, as a proof of concept this is brilliant, and we will be able to make pharmaceuticals and viral gene therapy agents that mimic the result. Some small molecule CCR5 antagonists (e.g. Maraviroc) are already approved for human use.

[DarklingAlice]

Decided to post this here for anyone who is interested.

This months Journal of Infectious Disease brings news of a setback in the field of CCR5 antagonists. In clinical trials of Vicriviroc (seriously who thinks of these names) it seems like HIV is already able to mutate beyond its ability to control. Gah, those hyper-variable regions are like an evolutionary win card, there has to be a way around them.

Characterization of Emergent HIV Resistance in Treatment‐Naive Subjects Enrolled in a Vicriviroc Phase 2 Trial

[Wolfy]

Didn't read...but looking at the Link, I notice the word Stem Cells.


Which means it'll never get through the morality barrier.


*sighs*

I could be dead wrong, of course...*shrugs*

[DarklingAlice]

Wrong kind of stem cells, Wolfy. You really should read the articles.

Anyway, the stem cell controversy is being bypassed. Give me a week and minimal lab facilities I can induce pluri-potency from your cells with just 4 enzymes. They're not as good as embryonic, but more than good enough to do what we need to do, and the whiny people can't say a thing against them.

[Oniya]

Anyway, the stem cell controversy is being bypassed. Give me a week and minimal lab facilities I can induce pluri-potency from your cells with just 4 enzymes.

*cheers* 

[Trieste]

*nodnodnod*

Yes, Wolfy, please read the actual article. :)

[The Dark Raven]

Also, my supervisor had read a paper a ways back saying that someplace in England (?) had a town that was nearly wiped out in the plague back in the middle ages, and that the descendants of those left seem to be somewhat resistant to HIV as well.

Eeeeenteresting.

[DarklingAlice]

Also, my supervisor had read a paper a ways back saying that someplace in England (?) had a town that was nearly wiped out in the plague back in the middle ages, and that the descendants of those left seem to be somewhat resistant to HIV as well.

Eeeeenteresting.

According to current theory that was the CCR5delta32 mutation at work. The higher prevalence of the mutation within Western European populations (almost 1%) is explained by the theory that it provides resistance to plague.