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Interviewee: Dr. Carl June, University of Pennsylvania
by Caroline Parnass
Before there was a way to screen donated blood for HIV, many people were exposed to the deadly virus through blood transfusions. But some rare individuals who received infected blood or other HIV exposures never developed AIDS.
When HIV manifests itself in the form of the disease AIDS, or acquired immune deficiency syndrome, the viruses attack the patient’s immune system, killing off the cells that fight infection. This is why most AIDS patients die from opportunistic infections, or infections that people don’t normally get unless they’re immunologically compromised, such as pneumonia or Kaposi’s sarcoma.
Over years of intensive study, scientists have discovered that an exceedingly small number of people have a natural immunity to HIV due to a single genetic mutation called delta 32, a deletion of 32 letters of DNA on the CCR5 gene, which codes for a molecule that HIV uses to enter immune system cells. This molecule is analogous to the cell’s gatekeeper, allowing things in and out of the cell; if it’s not there, the HIV cannot infiltrate the cell.
“In fact, this resistance is so robust that they can be exposed multiple times, even through blood transfusions from people who have HIV, and they don’t get infected,” says Carl June, professor at the University of Pennsylvania School of Medicine, and Director of Translational Research at the Abramson Family Cancer Research Institute.
Mimicking Mother Nature
Now researchers led by June are testing a new way to create that same natural immunity in people who already have HIV, and as they recently announced in the journal Nature Biotechnology, they have had encouraging success working with mice. “What our work did,” says June “was to find a way to disable this gatekeeper in a way similar to people who are born, those fortunate few, who have a natural immunity to the virus.”
June, along with Elena Perez, now at Children’s Hospital of Philadelphia, worked with other colleagues on a very powerful type of gene modification that uses zinc finger proteins or “ZFPs.” ZFPs are modeled after naturally occurring proteins that act as transcription factors, telling the cell which genes should be expressed and which should not. Co-author Philip Gregory, Vice President of Research at Sangamo Biosciences, where the technique for designing specific ZFPs was invented, says that with these proteins, “we’re able to switch on or switch off the expression of essentially any gene in the human genome.”
“A zinc finger nuclease can be designed so that it will find literally a needle in a haystack, one gene out of 30,000,” says June. The researchers had to test hundreds of ZFPs to identify one that could find and break the CCR5 gene, and prevent cells from producing the HIV gatekeeper molecule.
They then tested the modified cells in mice exposed to HIV, and observed that the mice that received the modified cells maintained normal immune systems, and had lower levels of the virus in their bloodstreams.
Hope for a New Treatment?
“This is the first time you could induce a permanent resistance of cells to the HIV virus,” says June. “The way we would normally do this is we would have to treat animals or people every day with medications. And this is a permanent treatment where, after this one time, the introduction of cells that have this HIV gatekeeper were able to fight off the virus. The other problem with the current therapies is that there are side effects,” notes June, “and those side effects are sometimes so severe that the patients have to stop taking medication, and then those patients really have no alternative.”
HIV has shown time and again that it’s good at mutating and thwarting treatments. But since this strategy shuts the door on the virus, the researchers are hopeful it may have an advantage there as well.
“This is the earliest stage of HIV infection,” says Gregory. “It’s the block to HIV entry into the cells it would normally enter.”
“Hit and Run”
Gregory explains that while the HIV treatment uses a viral vector to deliver the ZFP into cells, it’s not gene therapy in the traditional sense, because gene therapy relies on integrating foreign material into cells. “It’s like you put the virus in and it goes into the cell’s DNA and it stays there,” he says. Using viruses that integrate into genes has caused some major safety issues, even in successful gene therapy, he points out.
“We’re actually using a viral vector based on a common cold virus, called the adenovirus,” Gregory says. “The reason we chose it is that, other than having a viral coat on the outside, it’s a vector that does not integrate into the genome, so it’s rarely used in gene therapy applications these days because it only provides such a transient delivery mode. But in our case because we only need a transient delivery mode, it has the right characteristics for us.”
The researchers call this approach “hit and run,” and Gregory points out that the ZFPs are given to donated cells “ex vivo,” or outside the body. “The ZFPs are introduced, they carry out this genetic change, it’s permanent, but the carrier… the vector that gets the ZFPs into the cell, and the ZFPs themselves are washed out. And so what goes back into the patient is a modified cell that doesn’t have either the vector or the ZFP’s in it anymore.”
The research team is now planning safety tests for the treatment in HIV patients, using their own modified cells. June says in the short-term, they’ll start with small doses of modified cells and follow patients closely to monitor safety, and to see whether the cells are in fact exhibiting HIV resistance.
“In the long term, if this passes the first safety hurdles, we’ll then test the safety of giving multiple blood transfusions of immune cells,” June says “And if we can find that that approach is safe as well, then the next step would be to do this in their bone marrow cells so that the whole body would then become repopulated with cells that have natural resistance to HIV virus.”
This article was published in the July 29, 2008 edition of Nature Biotechnology, and the research was funded by the National Institutes of Health, NIST Advanced Technology Program, the Abramson Family Cancer Research Institute, Center for AIDS Research Cores and Sangamo Biosciences.
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