Dr. Richard Sutton from the Yale School of Medicine has spent much of his career searching for a cure to HIV, a virus that affects roughly 1.2 million Americans today. Dr. Sutton’s lab is currently trying to develop a viable solution to HIV by exploiting the virus’ method of cell entry: binding to CCR5 receptors on cells. Sutton’s focus on HIV replication has influenced his approach to studying the disease, which he discussed with the News Monday afternoon.
Q: Can you give us some background on how you’ve tried to find a solution to HIV?
A: Without [CCR5], HIV is dead. We’ve known now, for many years, that individuals who have a mutation in CCR5 don’t express CCR5 on their T cells and they’re relatively resistant to HIV infection. Why this is, we don’t know, but we know these people are normal, so if we can somehow reduce CCR5 levels or interfere with CCR5 function, we can make cells resistant to HIV.
Q: Have there been any specific developments using this approach?
A: Yes. In 2007, medication was approved, called maraviroc, that specifically targets CCR5 and it disrupts its function. It does work, but we never use it because it came out at about the same time that integrase inhibitors — other small molecule inhibitors of HIV — were approved. For maraviroc, we had to do a pre-test to see if the patient had circulating virus, which it would be active against. That cost $2,000, and a lot of physicians wouldn’t use maraviroc, so everyone started using integrase inhibitors. It never really gained market share. I don’t know if anyone will ever use maraviroc, to be honest, but it does work.
Q: What are some other ways to get rid of CCR5?
A: There are RNA enzymes which will cleave CCR5, but that doesn’t work very well. There are ways to essentially knock out the gene completely. There are some very specialized proteins called zinc-finger nucleases. These are fusion proteins that target very specific regions of DNA in the genome and also cut the DNA, so it makes the double-stranded cut in the DNA. Once the double-stranded cut is made into the genomic DNA, the cell has two choices: it can either die or it can repair it. If [the cell] repairs [the cut], it often makes errors in the repair. When it makes errors, that destroys CCR5. There are phase one clinical trials that are doing this exact approach for destroying CCR5 and the other coreceptor, CXCR4.
Q: Is targeting CXCR4 instead an option?
A: The problem with targeting CXCR4 is you cannot do it in progenitor cells — bone marrow stem cells — because if you do that, then there are all sorts of problems. If you want to target CXCR4, then you have to do it in mature T cells. That’s been done, it seems to work and there are mouse models to show that you can knock out CXCR4 this way using zinc-finger nucleases and then HIV cannot replicate.
Q: Is there a virus that has been comparable to HIV that we can reference as similar?
A: No. HIV belongs to the class of the retroviruses, and the retroviruses have been around for a hundred years that we knew about. But [HIV] is a relatively unique class of virus.
Q: What do you have to see, specifically, for you to be convinced that you have a successful solution?
A: Well, there are various steps. First, you do stuff with cells in culture. You can do these humanized mouse experiments where you put human cells into these immunodeficient mice, which you challenge with HIV and you see what levels of HIV replication you get. Then you can also move to non-human primates like Rhesus macaques and do similar gene therapy-type experiments. And then to humans.
Q: How close would you say we are to finding a viable solution for the eradication of HIV?
A: We do have a viable solution, it’s just hard to institute, even in the United States, which is essentially to prevent the virus from infecting new cells. We do have pretty good genes that will do that, or eliminate CCR5 from the cell surface. It is, in some cases, a matter of doing the clinical trials so that it actually works. You can’t just do things on the basis of n=1. I think the solutions are at hand. In terms of a prophylactic vaccine as a solution, which is obviously the preferred solution … not in our lifetime, unfortunately.