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Genetic mutation could lead to HIV treatment

Early safety trials underway

MOVE OVER X-MEN. A possible HIV treatment that harnesses the power human mutation is undergoing safety trials. Researchers are unsure if the process will actually work, but early safety trial results will be published in 2011. Credit: Corey Pierce

A possible HIV treatment that harnesses the power of a human mutation is in the midst of safety trials, bringing it one step closer to your doctor’s office. If it works the treatment would alter some of an HIV-positive patient’s blood to mimic a genetic mutation — called delta 32 — that makes a small percentage of the world’s population resistant or even immune to most strains of HIV.

“You have a needle in each arm and your blood comes out,” says Gwen Binder, a researcher at the AIDS Clinical Trials Unit (ACTU) of the University of Pennsylvania where the treatment is undergoing safety trials, describing the experimental treatment process. “They spin out your white blood cells and then they put everything [else] back in you. So it’s not actually taking a lot of blood.”

Next the T-cells are separated from the rest of the white blood cells. T-cells, a crucial part of the human immune system, are HIV’s primary target. Using a new gene therapy drug called SB-728-T researchers then modify the removed T-cells to synthetically recreate the delta-32 mutation, which changes the shape of the separated T-cells.

HIV is able to infect normal T-cells because the virus fits the shape of the T-cell’s surface — much like a lock and key. T-cells with the delta-32 mutation are malformed, missing an “innie” where HIV has an “outtie.” The result is that HIV no longer fits the lock; it just bounces off the cell.

“After modification of the white blood cells we expand them by culture to get a larger dose,” says Binder. There is also a series of tests to make sure the new white blood cells are sterile and otherwise safe. Then, a few weeks after the blood was drawn, the altered white blood cells are put back into the patient’s bloodstream.

Theoretically HIV will be unable to kill these altered T-cells. But even if that theory is confirmed it isn’t clear that the process will result in enough altered T-cells to have a noticeable effect in the body.

“We’re modifying one percent or less of the circulating population of T-cells,” says Binder.

If the modified cells multiply inside the study participants, as they did in the animal trials, their numbers will grow even as the virus kills off the unaltered T-cells. The idea is that the modified cells will be able to support a healthy immune system — or at least a healthier immune system.

The safety trials for this new treatment, which began in February, are expected to be completed by December 2010, with results to be published sometime in 2011.

In addition to a new treatment there is also hope that mimicking the delta-32 mutation could lead to a cure. About two years ago an HIV-positive US expatriate living in Berlin received a bone marrow transplant from a donor with the natural delta-32 mutation. Subsequent tests have been unable to detect HIV in his bloodstream. The transplant appears to have, for all intents and purposes, cured him. Could SB-728-T likewise be used to create delta-32 bone marrow for other people with HIV?

“We’re certainly not proposing using chemotherapy in healthy individuals,” says Binder, adding that the bone marrow transplant process is far too risky, with mortality rates between 10 and 50 percent. To find out if the phenomenon could be reproduced synthetically in others Binder says researchers would have to find patients with HIV who have cancer and are already in need of chemo and a marrow transplant.

In the meantime Binder and the team of researchers led by ACTU director Pablo Tebas are enrolling HIV-positive volunteers in their study at the University of Pennsylvania. They’re starting with six people for whom antiretroviral drugs are no longer working — people who are running out of treatment options. If that goes well, they will enrol six more HIV-positive volunteers with well-controlled HIV who are already on antiretroviral medications.

There’s been no shortage of volunteers, says Binder, in spite of the fact that participation in the study is not without risk. Although the treatment has been used successfully in mice and in human blood samples, this is the first time it’s been attempted in humans.

Perhaps the riskiest part of the study will occur when the second group of volunteers go off their antiretroviral medications for about 16 weeks.

According to meeting minutes of the US National Institutes of Health Recombinant DNA Advisory Committee, “Although cogent arguments were presented suggesting that a short interruption of [antiretroviral medication] may not pose a significant risk, current evidence from the literature indicates that it is not without some risk.”

The minutes also point out that in spite of the risk the second group of volunteers will be taking the experimental treatment that could turn out to have no benefit to them.

“We have to be very careful in a [safety trial] to not give patients the impression that we’re giving them a treatment or a therapy that might help them,” says Binder. “We’re very clear that this is just an initial phase to look at safety.”

Despite those cautions the research team will certainly be looking for signs that the treatment is working when the data is ready for analysis in 2010/’11. That will include looking at how HIV infections progressed during the trial and to what extent the altered T-cells have died out, persisted or even flourished and multiplied.

“If the study goes well, part of the standard clinical plan would be to move on to a phase two clinical trial that’s designed to evaluate efficacy,” says Binder. A phase two trial would involve up to 300 patients and, if successful, would lead to a phase three trial with up to 3,000 participants. The phase three trial is the final requirement for approval by the US Food and Drug Administration (FDA).

The whole FDA approval process takes on average of eight years which means that — if it is approved at all — people living with HIV/AIDS could see the treatment available by 2017.