To understand what's going on, I'm going to have to explain a few things:
•HIV attaches to the CD4 receptors (and their co-receptors) on our CD4 immune cells (aptly named) and uses them to enter the cell and thereby make copies of itself
•A small percentage of people of Northern European descent (1-2.5%) have an inherited genetic mutation (delta 32 mutation) that alters the form of their CD4 receptors (actually, the co-receptor CCR5) making HIV infection (and replication) very difficult, if not impossible.
Could we artificially alter/block these receptors with medications? What would be the side effects? Do the people with the natural delta 32 mutation face any unrelated challenges? There was a lot of concern in the medical/research community about this, so this new knowledge was met with caution. A few pharmaceutical companies began examining possible agents. Maraviroc was studied and finally approved for use as a CCR5 antagonist (a drug that blocks the CCR5 co-receptor).
Concerns about blocking the receptor proved to be unfounded as maraviroc has become a great drug in the anti-HIV arsenal. Though, one downside to blocking the CCR5 co-receptor is that it makes a person more susceptible to West Nile disease should a person be exposed to the West Nile Virus.
At the same time as all of this, a long-time HIV+ patient in Berlin was diagnosed with a form of leukemia and required a bone marrow transplant. His ingenious physician, knowing about the delta 32 mutation in some people, looked through the compatible matches to see if any had the mutation. And, lo and behold, he found one. Which was extremely luck given the rarity of the mutation in the population. And HIV seemed to have been wiped out in the patient
At CROI 2008 (a big HIV conference), the paper on the Berlin patient was presented, but reaction was muted as many felt that HIV would still be hiding in reservoirs in the body and it would only be a matter of time before HIV "re-appeared" in the blood stream. It took a few years more, but when further evidence showed the Berlin patient was still free of HIV, people started to really stand up and pay attention. And he is still HIV-free. This has also motivated further pharmaceutical research on ways to disrupt the CCR5 co-receptor.
I know, you're probably wondering what zinc fingers have to do with this....I'm getting to that now!
One pharmaceutical company had been looking at ways to more permanently alter the co-receptor rather than just continually provide a drug that blocks it. They had been looking into zinc finger nucleases (ZFNs) which are basically scissors that cut the piece of DNA/gene that is responsible for making the CCR5 receptor. In the past, studies had not been so favourable as the altered CD4 cells weren't able to be maintained in the body.
Fast forward to this past CROI 2011 which was just held. A group of researched presented a paper on the successful proof-of-concept use of ZFNs, in addition to HAART, in treating HIV. They found that:
•The treatment was safe and well tolerated.
•Their were CD4 cell count increases (the patients in the trial were HIV+, on HAART, with a low CD4 count) in 50% of the patients and a fixable reason why the other 50% didn't respond that could be addressed.
•These altered CD4 cells were maintained in the body throughout the study. Not only maintained, but with huge increases meaning that the altered cells were growing in the body.
•Three out of five of the responders had a normalized CD4/CD8 ratio which is a good sign of a healthy immune system
•Great news: CD4 altered cells were found in the rectal mucosa at all testing times throughout the trial. It also was found in other mucosal sites and the gut tract (another good sign!)
(•these patients will be followed for life to look at long term ramifications (positive/negative))
This definitely opens up some new research possibilities, but there are still a lot of questions and concerns that also need to be addressed:
•long term effect: will it help or hurt long term prognosis?
•future studies of people already on treatment would require a Structured Treatment Interruption (which we know to generally have a negative effect on long term prognosis and not advised). Will future studies even be able to be ethically approved in light of this?
•what is the proper dosing?
•will this work in people with a detectable viral load who are not on treatment? (A small trial is underway now in San Francisco to look at this)
•will this allow people to stop HAART or avoid it altogether?
We should be very careful not to overreach with these data. Many people are throwing the "cure" word around when talking about this study, but this is just a very preliminary effort to start answering important questions toward that goal. But it's much better writing about/hearing good news than bad.
This new field will probably create several new treatment mehanisms, and perhaps even preventative. Whose to say a person at extremely high risk of HIV infection would not benefit from a reprogramming of her CD4 cells to be more resistant to infection? Like I said, possibilities.....
Posted on
Fri, March 18, 2011
by B.J. Caldwell
filed under