Genetically modifying the stem cells of HIV patients may one day prove to be an effective, one-time therapy against the hard-to-kill virus, according to the results of a proof-of-principle trial published this week in Science Translational Medicine.
|Human Immunodeficiency Virus
Image: Wikimedia commons,
In contrast to the widely used highly active antiretroviral therapy (HAART), which patients must continue for their entire lives to control the virus, such a genetic treatment has the potential to be “a single administration therapy,” said bioengineer David Schaffer of the University of California at Berkeley, who was not involved in the trial, “where you introduce [a gene] into somebody’s cells, and it stays there the rest of their lives. [That] has the potential to be a major plus,” eliminating many of the toxic effects and financial costs of HAART.
Because of these potential advantages, gene therapy — the integration of new genetic material into a patient’s genome — has been proposed as a treatment for HIV. In past clinical trials, however, the new genetic material has failed to persist more than 8 months or a year. But taking advantage of a golden opportunity in which a handful of HIV patients had to undergo bone marrow transplants, molecular geneticist John Rossi of the City of Hope cancer center in California and his colleagues introduced three different therapeutic genes into patients’ blood stem cells, then found evidence of those genetic elements in the blood up to 24 months later.
“It showed us that you can introduce genes into somebody’s blood cells, and it can stay around for years,” said Schaffer, who wrote a perspective about the paper.
“That’s a major finding,” Rossi added. While the number of cells expressing those genes was too low to provide any therapeutic benefit, it’s “proof of principle” that gene therapy may provide long-term HIV treatment, he said.
These results come in the wake of a recent report on the miraculous “Berlin patient,” who appeared to be cured of HIV after receiving a bone marrow transplant as a treatment for leukemia from an individual with a mutation in the CCR5 gene, which codes for a coreceptor used by HIV to enter cells. Although “we don’t really know what resulted in the ‘cure’ that that patient had,” said immunologist Carl June of the University of Pennsylvania School of Medicine, who did not participate in the study, it is a “really intriguing” idea that the CCR5 mutation could have played a role in preventing the virus from coming back.
Finding marrow donors that are a match to HIV patients and have such a mutation, however, is not easy, he added. But a clever twist — manipulating patients’ own cells to carry such therapeutic mutations — “is going to, in principle, allow that to happen.”
The trial patients had contracted AIDS-related lymphoma, and were thus in need of a marrow transplant — in this case, from themselves. Blood stem cells were extracted from the patients’ bone marrow, then reinjected into their bodies after they had undergone chemotherapy to destroy the malignant cell population. Before the cells were reinjected, however, the researchers inserted three therapeutic genes, including one that targets CCR5, into some of the cells that rendered them HIV-resistant.
“The idea was that any single agent that you put as an antiviral agent is probably not going to be effective [because the] virus would mutate around [it],” Rossi said, “but the combination of all three would make it very difficult for the virus to escape.”
In addition to demonstrating the long-term expression of these genetic elements, the researchers found no evidence of adverse effects associated with the manipulation.
The next step is to determine how many blood cells must be genetically modified in order to truly beat back HIV, said hematologist Gero Hütter of Charité University Medicine Berlin in Germany, who co-authored The New England Journal of Medicine article about the Berlin patient, “but today it’s not clear how high this proportion should be.” Indeed, “determining that’s going to be really tricky,” Rossi said. “It may vary from individual to individual [and] we don’t have animal data that would suggest” an answer. But they’re working on it, he said, using humanized mouse models as well as non-human primates. Eventually, he said, if done right, a successful gene therapy treatment “could eliminate the daily need for antiretroviral therapy.”