AUSTIN, Texas — Researchers at the University of Texas and Stanford University have blocked HIV from invading healthy cells in the laboratory, saying the work could lead to treating patients without drugs.
The scientists knocked out a gene involved in HIV and inserted three genes that help the cells resist the virus in a process they call “targeted stacking.” The research was published this week in the journal Molecular Therapy.
The process is three to five years away from being tried in humans and mirrors recent strategies to attack HIV, the precursor to AIDS, at the genetic level. But the UT and Stanford scientists said their method is more precise — and more effective.
It combines two different approaches — using a zinc protein to inactivate an HIV gene and then adding blockers to fight off both types, or strains, of the virus.
These “zinc-finger nucleases” act like “a molecular scissors that can be used to cut out a gene in the human genome, and insert other ones in its place,” said Sara Sawyer, a co-author of the study and an assistant professor of molecular genetics and microbiology at UT-Austin. “That is exactly what we did. We cut out a gene that HIV needs, and replaced it with three genes that work to block HIV replication. This makes T-cells virtually resistant to HIV infection, at least in the lab.”
Her collaborator at Stanford, Dr. Matthew Porteus, said, “It’s like a Reese’s Peanut Butter Cup. We’re fusing two approaches.”
Such gene manipulations represent the next wave of HIV research and “could contribute toward a cure for HIV,” said Dr. Paul Spearman, a research professor and vice chairman for research in the Department of Pediatrics at Emory University in Atlanta.
“It’s a clever way of enhancing the ability of zinc nucleases in blocking HIV infection,” said Spearman, who isn’t involved with the UT and Stanford team. “It’s a really promising approach.”
The research builds on work done by Sangamo BioSciences Inc. in Richmond, Calif., which is conducting two human trials that involve taking cells from patients, cutting out a gene that is critical for HIV infection and returning the cells to the patients, without adding HIV blocker genes.
“I would argue that the pure gene knock-out approach is more precise,” said Philip Gregory, Sangamo’s vice president for research and chief scientific officer. And it’s simpler than adding genes to an altered cell, he said.
“We think it’s a much easier argument to take away something that is permanent — because it’s a genetic change — and should add no further burden to the cell,” Gregory said. He added that the trials are going well and by year’s end should produce answers on whether the process works.
Spearman said that while Sangamo’s trials are important, he also is hopeful about the UT and Stanford work. “You could easily say this approach, if translated into human trials, could provide more potent inhibition of HIV,” he said.
The process wouldn’t eliminate HIV in patients, Sawyer said in a statement, but “it would provide them with a protected set of T cells that would ward off the immune collapse that typically gives rise to AIDS. It would be an alternative way to manage the disease.”
No one yet knows how much the therapy would cost versus the cost of taking HIV medications for life, which can easily run above $20,000 a year. Gregory said his company believes the charge would be competitive with drug costs. People with HIV can now take one pill that contains several drugs as an all-in-one cocktail. The UT and Stanford team modeled its approach on that concept, Sawyer said.
The team is now moving toward animal testing, said Porteus, a Stanford associate professor of pediatrics who met Sawyer in 2008 and decided to collaborate. He worked with Sangamo several years ago.
Drugs have enabled HIV patients to “live a normal life,” Porteus said. “Nonetheless, it does require taking a medication for the rest of your life, and those medicines are not without side effects.”
There also are potential drawbacks to manipulating genes. For example, cutting out a gene could cause a break elsewhere, leading to cancer or other problems, the researchers said.
Their work was funded by a $400,000 grant from the American Foundation for AIDS Research, Porteus said. And while it is costly to develop a therapy that can be used in humans, he and Sawyer said they are hopeful. “HIV is such a tremendous burden on the planet,” Sawyer said, “there is no shortage of money to … develop a technology like this.”