December 1st, World AIDS Day, and we find ourselves reflecting on how nearly 30 years after it first reared its ugly head, HIV is still newly infecting some two million adults a year, and despite millions of dollars and hours of research, the virus has proved elusive and slippery to vaccine developers. But an alternative path is starting to open up: gene therapy.
A new study published in Nature on Wednesday, describes how Nobel Laureate David Baltimore, a virologist and HIV researcher at the California Institute of Technology (Caltech) in Pasadena, and colleagues, inserted a gene into the leg muscles of lab mice bred to be susceptible to human HIV, that caused them to make a broad range of antibodies that protected them against exposure to HIV.
This is still a long way from developing a gene therapy approach that works in humans, but it’s a start. In fact it’s more than a start because this has been done before, with monkeys. In 2009, researchers at the Children’s Hospital of Philadelphia in Pennsylvania, were the first to raise the possibility of gene therapy for preventing HIV when they showed it was effective in preventing transmission of the simian immunodeficiency virus, which is similar to HIV but infects monkeys.
Both teams are now planning to test the method in humans.
Although it seems extreme to use gene therapy as a way to prevent an infectious disease as opposed to an inherited disease, if it works, and we still have no vaccine, then it may be an effective alternative, as long as it is safe.
So why is it proving so hard to find an effective vaccine against HIV? Well, it’s not as though scientists haven’t been trying. In fact, in 2009, they nearly got there, when a large trial in Thailand showed an experimental vaccine protected about one third of the people who received it from HIV infection. But one third is not high enough to stop transmission in the general population. So scientists are now back at the “drawing board” trying to improve the vaccine.
The reason HIV is proving so elusive to vaccine developers is because to make a vaccine you have to use either all or parts of an inactivated virus to induce an immune response to make antibody proteins against the real live virus. But HIV is a slippery character: it manages somehow to cloak or disguise most of the easily-recognized bits of itself that the antibody proteins are programmed to grab onto (it hides its grab-handles if you like).
Scientists are working hard to find at least one molecule that makes the immune system respond with a broad range of antibody proteins that can find grab-handles in all the various mutated forms of HIV: but the challenge is proving to be very tough. On the one hand they have found a broad range of antibodies that work against HIV, but on the other hand, they can’t get the immune system to produce the required response to make them all.
The risk with gene therapy is that once you have inserted the gene, if it goes wrong and starts causing other side effects you hadn’t bargained for, how do you switch it off? So the journey down this path has to be optimism tempered with caution.
In the Nature paper, Baltimore, who is also president emeritus and Robert Andrews Millikan Professor of Biology at Caltech, and colleagues, describe how they developed a gene therapy approach to HIV prevention that they call “Vectored ImmunoProphylaxis”, or “VIP”.
Mice are not naturally susceptible to HIV, so the researchers used mice that had been engineered to carry human immune cells that are able to grow HIV. (HIV wreaks havoc by invading host cells, merging with their DNA, then reprogramming them to behave in a way that helps the virus replicate and spread).
To insert the gene, Baltimore and his team used an adeno-associated virus (AAV), a small, harmless virus frequently used in gene-therapy trials, as a carrier to deliver genes bearing instructions for making the appropriate broad range of antibodies.
They injected the AAV and its payload into the leg muscle of the humanized mice, and found the muscle cells were pumping out the antibodies into the mice’s bloodstream.
Remarkably, those antibodies, which the mice were producing in high concentrations after just one injection, were enough to protect the mice from HIV given to them intravenously. And equally remarkable was the fact they continued to produce high concentrations of the antibodies for the rest of their lives.
The researchers were keen to point out that what works in mice does not necessarily work in humans, and there is still a long way to go before we will know for sure whether this approach bears out the hopes raised by this study.
But they are optimistic. They believe the large concentration of antibodies the mice produced, together with the finding that a relatively small amount of antibody has provided protection in the mice, may well translate into protection against HIV in humans.
“We’re not promising that we’ve actually solved the human problem,” Baltimore said in statement from Caltech. “But the evidence for prevention in these mice is very clear.”
“If humans are like mice, then we have devised a way to protect against the transmission of HIV from person to person. But that is a huge ‘if’, and so the next step is to try to find out whether humans behave like mice,” he added.
In their Nature paper the authors also describe how the VIP method worked even when they exposed the mice to higher amounts of HIV. The first test they did was with a virus dose of one nanogram. This is usually enough HIV to infect most mice who receive it. When they found the treated mice were able to withstand that dose, they continued to raise it until they reached 125 nanograms, and the mice still withstood it.
First author Alejandro Balazs, a postdoctoral scholar in Baltimore’s lab, said:
“We expected that at some dose, the antibodies would fail to protect the mice, but it never did – even when we gave mice 100 times more HIV than would be needed to infect 7 out of 8 mice.”
“All of the exposures in this work were significantly larger than a human being would be likely to encounter,” he added.
Balazs said it was more likely that this result was down to the type of antibody they were testing rather than the VIP method itself. However, he points out that it is the VIP that enabled the large amount of the powerful antibody to get into the mice’s bloodstream and beat the virus.
The other advantage is that VIP is a “platform” approach; you can change the payload to be other, perhaps even more powerful, antibodies, leaving open the door for scientists to find these and use VIP to deliver them. And not only against HIV, but also other infectious agents.
The team is now planning to test VIP in human trials. First they want to find out if the AAV vector can program muscles in humans to make the levels of antibody that would be needed to protect against HIV.
Balazs has high hopes of success:
“In typical vaccine studies, those inoculated usually mount an immune response – you just don’t know if it’s going to work to fight the virus,” he explains, but, “In this case, because we already know that the antibodies work, my opinion is that if we can induce production of sufficient antibody in people, then the odds that VIP will be successful are actually pretty high.”
Written by Catharine Paddock PhD