There's a mantra in the AIDS field: HIV infection can be managed with antiretroviral drugs, but it can't be cured. Now a small success in a new gene-therapy study suggests that it may be possible to derail the virus once and for all.
In a study published today in Science Translational Medicine, researchers from the City of Hope National Medical Center, a medical research institute in Duarte, California, describe how they removed immune stem cells from four cancer patients also infected with HIV, stitched in genes to outwit the virus, and transplanted the fortified cells back into the men. The genes have continued to work, albeit at extremely low levels, for up to 2 years. The altered stem cells also matured and, as hoped, diversified into different types of immune system cells that HIV infects. Ultimately, the researchers hope the anti-HIV genes can clear the virus or, failing that, render it harmless.
"It was a very carefully conducted study, and it's a proof of concept that it's doable," says Carl June, a medical oncologist who is conducting similar gene-therapy studies with HIV at the University of Pennsylvania School of Medicine. "Stem cells until now have been very resistant to this approach."
As City of Hope's John Rossi, John Zaia, David DiGiusto, and colleagues describe in their new study, there is no evidence that the treatment helped any of the men control their HIV infections. But that wasn't the point: The men needed a stem-cell transplant to treat their non-Hodgkin's lymphomas, and the anti-HIV genes were like hitchhikers, introduced by the researchers to see how they'd fare. Importantly, no serious side effects surfaced, and the cancer in every patient has remained in remission.
Earlier clinical studies the group conducted with the same strategy made little headway, but now the researchers have overcome two key obstacles, says Rossi, a molecular geneticist. One is that they managed to stitch the anti-HIV genes into a high percentage of the appropriate stem cells. The other is that the cells lived for a long time. "If we could increase the number of modified cells by 10- or 100-fold, we might be able to stop the virus itself," says Rossi.
The approach essentially trains the body to make its own anti-HIV drugs and disables a key receptor the virus needs to establish new rounds of infection. To accomplish this feat, the researchers first removed immune stem cells from the patients and destroyed most of their remaining immune system with dangerous "ablative" therapy that is a standard part of the transplant procedure to treat the lymphoma. Then, in test-tube manipulations, the team added three genes to the immune stem cells' DNA: one that cripples the CCR5 receptor that HIV exploits to enter the cell (this mimics a successful transplant recently done in Berlin with a much discussed patient who apparently was "cured" of his HIV infection), and two others that disable viral genes and prevent HIV from copying itself. This makes it increasingly difficult for HIV to find new targets and mops up any new virus produced.
Rossi has several ideas about how to improve the experiment. As a safety feature, this study gave patients unmodified stem cells and ones tweaked with HIV genes. He and others believe the unmodified cells likely competed with the engineered ones for "space" and made it difficult for them to survive. "That puts the genetically modified stem cells behind the eight ball," says Rossi. In future experiments, he hopes to transplant only modified cells.
Rossi expects the field to continue to advance one step at a time. Although researchers pursuing a cure would ideally like to clear the body completely of HIV, that's an extremely high hurdle, as the virus can lie dormant for many years inside of chromosomes, undetected by the immune system and invulnerable to drugs. So a gene-therapy "success" at first might only be defined as a treatment that makes antiretroviral drugs unnecessary for several months or a few years, relieving patients of side effects like cardiac and neurological problems. "It would be a huge improvement in the treatment of the disease," he says.
June is more optimistic still. "Now it's just a problem of engineering, where we need to work out the details," June says. "I don't see any show stoppers."