From the respected medical journal…err the Wall Street Journal:
The startling case of an AIDS patient who underwent a bone marrow transplant to treat leukemia is stirring new hope that gene-therapy strategies on the far edges of AIDS research might someday cure the disease.
The patient, a 42-year-old American living in Berlin, is still recovering from his leukemia therapy, but he appears to have won his battle with AIDS. Doctors have not been able to detect the virus in his blood for more than 600 days, despite his having ceased all conventional AIDS medication. Normally when a patient stops taking AIDS drugs, the virus stampedes through the body within weeks, or days….
The breakthrough appears to be that Dr. Hütter, a soft-spoken hematologist who isn’t an AIDS specialist, deliberately replaced the patient’s bone marrow cells with those from a donor who has a naturally occurring genetic mutation that renders his cells immune to almost all strains of HIV, the virus that causes AIDS.
This story has received much media attention.
Here’s the big concept. The cells in your immune system that voraciously gobble up invaders, macrophages, have a protein on their surface called CCR5. CCR stands for chemokine receptor. Chemokines and chemokine receptors are how your immune cells talk to one another when fending off an invasion—a cellular game
of Marco-Polo.
Macrophages are constantly crawling all over your body, including just below the skin. When you have sex with an HIV positive individual, some of their virus can enter your body—through mucous membranes or small cuts in the skin. Your macrophages dutifully chase after the invading virus. When they meet, the virus turns tables on the macrophage—using the viral gp120 protein as a key to open up the CCR5 protein, using it as a door into the cell. Once safely inside the macrophage, the HIV virus can produce billions of copies of itself, per day per cell. Macrophages are hardy cells. They easily survive, even while pumping out virus.
In other words, the HIV gp120 protein in Rick Moranis, the macrophage’s CCR5 protein in Sigourney Weaver. Putting the two of them together? Extremely dangerous.
Eventually, the virus gp120 protein mutates until it can open the CXCR5 protein on the surface of CD4+ helper T cells (the generals of your immune system) like it opened the CCR5 protein on the macrophages. When this happens, the virus can efficiently enter into the T cells. These cells are much weaker than the macrophages, and die off when stressed by being forced to produce new virus copies. When enough T cells die off, you have AIDS.
About 1% of the population, thanks to having two mutant copies of the gene, completely lack the CCR5 protein. With no CCR5 protein, there is no way for the HIV virus to enter macrophages. Thus, these people are immune to HIV infection. Somewhere around 10-15% of the population has one bad copy of the CCR5 gene, and therefore have delayed progression to AIDS, as their macrophages are more resistant to infection than those with two good copies of the gene.
Whew.
The bone marrow makes all the cells in the blood. If you have a blood cancer, the last ditch treatment is to kill off your (cancerous) bone marrow, and replace it with bone marrow from a healthy donor. The patient described in the article had leukemia (blood cancer) and was HIV positive. To treat his leukemia, his bone marrow was killed off. His donor marrow was mutant for CCR5. Now six hundred days after receiving the CCR5-lacking bone marrow, his doctors cannot detect HIV virus in his blood—even though the patient is no longer on drug treatment for HIV.
As much as I respect the awesome power of Rupert Murdoch and the Wall Street Journal, I’d like to see some of the claims here undergo a bit of scrutiny, as they would if published in a proper medical journal.
This is a case report, of an experience in a single patient. I’m loath to declare that since “[d]octors have not been able to detect the virus in his blood for more than 600 days” this patient is cured from AIDS, let alone consider this as proof that transplantation of CCR5 mutant bone marrow will cure everyone with HIV of the infection.
If this is generally true—transplantation with CCR5 lacking bone marrow can “cure” you of HIV infection—big, but solvable, problems remain.
First, donors lacking CCR5 are rare—about 1% of the population. And it’s already difficult to find CCR5 normal bone marrow that is a close enough match to transplant. This could potentially be solved by using gene knockdown, to turn off the normal CCR5 genes most donor bone marrow contains.
The bigger problem is, undergoing a bone marrow transplant is both dangerous an unpleasant. The first step? A lethal dose of irradiation. If the bone marrow transplant doesn’t work, you die. Horribly. If the bone marrow takes, but then starts attacking your body, you die even more horribly. If it works perfectly, you’re still at a heightened risk of a whole slew of cancers, thanks to all the irradiation.
I’d stick with drug therapy, if given the choice.
Doctors say the case gives hope for therapies that artificially induce the Delta 32 mutation, not that bone marrow transplant would be the new cure. who’s proposing that? of course it’s out of the question.
I think that you’re missing the point here. This is not being proposed as a practical cure. That would be ridiculous – it’s hazardous and finding the necessary matches would be rare. What this does do is provide the basis for some new examinations of potential treatments.
bone marrow transplants as viral cure is, indeed, absurd. but the fact that research has identified so much about hiv and an increasing amount about how to make the human body resistant is heartening.
also, wouldn’t it be possible to artificially grow hiv resistant cells farmed from that 1%? or am i just fantasizing…
ellarosa, wench and douglas:
Agreed. I get it. Although I think you might consider transplant as a last-ditch effort to treat drug-resistant HIV.
What I’m having trouble with is repeating the initial observation. Does transplant with CCR5 negative bone marrow really cure HIV? I have my doubts. Macrophages are tough–easily surviving the radiation. So, provirus containing phages likely still exist in this patient. It might take years, but I fear his HIV will come back.
Deleting CCR5 in an adult patient’s macrophages, body-wide, seems grossly impractical. I cannot fathom a way of doing it, and I spend a lot of time thinking about gene therapy.
Easier might be devising a CCR5-inactivating small molecule as an additional drug therapy…
Thanks for explaining, Science!
A characteristically excellently erudite essay, but one small style point: you didn’t mean “loathe” but “loath” without the “e.”
http://englishplus.com/grammar/00000238.…
Loath or Loathe?
Loath is an adjective meaning “unwilling.” It ends with a hard th and rhymes with growth or both.
Loathe is a verb meaning “to hate intensely.” It ends with a soft th like the sound in smooth or breathe.
Examples: He was loath to admit that he was included in the deal.
(He was unwilling)
Alex loathes spiders.
(Hates them intensely)
Thank you Tim Appelo. I’ve made the correction.
(I also looked up erudite.)
It is 2008 and I’m just learning that there are people out there that are naturally immune to H I fucking V? How long have we known about this?
Am I dumb? Seriously, I would think the moment someone realized this it would be the biggest headline ever. Where was I?
Also, will HIV someday mutate to be a threat to non-CCR5 thingamabobers?
How long before personal ads appear with the phrase “CCR5 neg.”?
Mike in MO:
OOH! You made my day with both your comments. Seriously. I am one very happy nerd right now.
Ready to have your mind blown? For almost any infectious disease, a small percentage of the population will be totally immune–thanks to these sorts of mutations. Part of the reason this wasn’t huge news, is scientists *expected* a small percentage of human beings to be immune to HIV.
It isn’t just HIV. A subset of the population is immune (or at least resistant) to smallpox. Cholera, TB, Malaria just about anything, you can find some people running around with mutations conferring protection upon them.
This is the real power behind evolution–the mutations. If you get an evolutionary biologist drunk enough, they’ll start telling you that most organisms allow a certain rate of mutations to occur, to produce this exact situation–where there is always an Omega Man subset of the population capable of surviving epidemics. In other words, mutation is selected for as a trait.
Will HIV ever mutate to get around CCR5 null people’s defense? Not unless there are many more people without CCR5, for the same reason that malware writers stick with windows rather than Mac OS X….
I really don’t know how much of the original proposal to believe, it doesn’t match any of the HIV seminars I’ve sat in on or the papers we’ve reviewed in journal club.
Point me to the underlying science and multiple repeatable studies and I might believe it.
god bless the plague.
Jonathan Golob, your ability to ‘splain complicated shit is a superpower.
Mike In Mo,
The Delta 32 mutation was discussed on a PBS special years and years ago called “Secrets of the Dead” about the Bubonic Plague.
As a microbiologist, I think you did a good job of describing the science, Jonathon.
If I could simplify what you said for people who still didn’t follow, I guess I would put it like this:
The HIV virus attacks immune cells using a skeleton key, (the gp120 protein), to open a sort of lock on the cell, (the CCR5 receptor). A small number of people have immune cells that have changed some of their locks, (those with one copy of the mutant gene), and an even SMALLER subset of the population have had all their locks changed, (those with two copies of the mutant gene).
If it turns out to be true, I wouldn’t be too surprised if this treatment ultimately works. Even if the patient isn’t free of the HIV virus, he’ll have enough healthy T-cells to function like a normal human being, albeit, one who’s undergone a pretty major medical procedure.
So, instead of the usual 1-5 percent death rate from an operation like this, you’re saying it’s higher, Arsenic7?
No I’m not saying that, nor am I a medical expert in any way shape or form, so I can’t comment on that. Really I was just trying to put everything the slog post said into a metaphor.
That said, people with AIDS already have a weakened immune system and aren’t the normal demographic for bone marrow transplants, though I’m sure many receive them. I wouldn’t be surprised if there were complications involved that aren’t normally present in a patient with Leukemia alone.
But I do believe this procedure may result in more interest in using stem cell and genetic research as a possible treatment for AIDS down the road.
I remember when they tried bone marrow transplants as an AIDS cure a few decades ago (probably before they tested donors for the mutation). The problem was that AIDS camped out in the dendritic cells of the patient. The dendritic cells weren’t killed by the radiation and then reinfected the patient.
Dendritic cells are an antigen presentation cell for the immune system. A very loose analogy would be that they put up the Wanted posters for nasty things that the immune system is targeting.
I always wondered if someone tried a bone marrow transplant in combination with some treatment which specifically targeted the patients dendritic cells.
Well that’s kind of what this did. It basically allowed for the creation of new, immune, dendritic cells. Immune cells are created in the bone marrow, just like all other blood cells.