When I learned about this, my jaw dropped. It almost felt like the old light bulb joke: is it easier to screw in the bulb or to turn the ladder? It turns out, when it comes to HIV, the question is not so ill-posed.
HIV infects white cells in our blood called T-cells. It captures a receptor on the cell surface called CCR5 (it's a little more complicated than that, more like trying to unlock handcuffs, with multiple pieces that need to fall into place), and once it grabs it, it docks with the cell and infects it. T-cells are part of our immune system and they attack the virus as well. Ever since I started working on HIV, the problem, from my end, has been: how can we elicit T-cells and antibodies able to recognize (and destroy) the virus?
As I have explained in earlier posts, this has been a challenging task.
I've talked extensively about HIV genetic mutations, but, as you know, human genomes carry mutations too. And here's the interesting finding: a mutation called Delta 32 on the CCR5 receptor gene has been identified and linked to a delay in progression to AIDS. In addition, individuals who have both gene copies mutated, are highly resistant to HIV infection [1]. The mutation changes the receptor on the T-cell in a way that the virus is no longer able to dock with it. And if the virus can't dock with the T-cell, it can't infect it. It slips away until the immune system clears it.
So, can we switch the problem around, as in: instead of making T-cells able to recognize the virus, can we make the T-cells unrecognizable to the virus?
As with many scientific queries, the answer is maybe [2]. Sangamo BioSciences, a California based company, has an ongoing Phase ½ and two Phase 1 trials using gene therapy to introduce the mutation in HIV infected patients. The Phase 1 trial at the University of Pennsylvania just recently announced that one of the subjects in the study went off the antiretroviral drugs and, after an initial spike, within days viral loads dropped to undetectable.
The advantage, if this turns into a permanent eradication of the virus, is the possibility of weaning patients off antiretroviral drugs, which have toxic long term effects and can also develop harmful, drug-resistant strains. Right now HIV infected patients have no choice other than life-long therapy.
The flip side is that gene therapy introduces permanent genetic changes and as such, carries risks. There are also numerous caveats (for example, which cells are the best targets), which are thoroughly discussed in [2]. I only have two cautionary comments to add.
My first thought is that gene therapy is an expensive and invasive procedure, and even if it does develop into a successful means to defeat the virus, it will unlikely become available to patients in Sub-Saharan Africa. And two thirds of the people currently living with HIV/AIDS are in Sub-Saharan Africa. This is why a vaccine that is not only able to prevent the infection, but also to protect the immune system in case the infection has already started, still remains the best and most affordable option.
Second: it's not clear to me whether the results are permanent. You see, HIV is a nasty little virus. It can infect a single cell and stay dormant for years. That is, for years you don't see it, until it wakes up again. And when it wakes up, it can be deadlier than before.
If this "cure" doesn't completely wipe out the virus, the risk of selecting stronger and more resistant strains is real. HIV replicates so rapidly, and with such a high mutation rate, that it might evolve a new strain able to "grab" the defective receptor. And that would mean a new, tougher viral strain to defeat.
[1] Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, & Berger EA (1996). CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science (New York, N.Y.), 272 (5270), 1955-8 PMID: 8658171
[2] Van Lunzen J, Fehse B, & Hauber J (2011). Gene therapy strategies: can we eradicate HIV? Current HIV/AIDS reports, 8 (2), 78-84 PMID: 21331536
Photo: wind sculpture, Santa Fe, NM.
That's really interesting. It does seem that since they are modifying T-cells rather than the production of T-cells there is more of a chance for the virus to hide as you say.
ReplyDeleteYes. The risk is present either way, as a vaccine could also leave out a few selected strains, but because you can vaccinate the whole population, the chances of the "survivors" being transmitted at that point are low (well, there are models to check the likelihood, anyways). Gene therapy will not be available to the entire population, and it seems to me that it would modify the immune system in a way that the virus could bounce back in a nasty way...
ReplyDeleteNonetheless, it's interesting and worth seeing what will happen next. :)