Study says genetic trick slows AIDS virus growth

For the first time, researchers have slowed and possibly stopped the AIDS virus from reproducing in patients by using a gene therapy that tricks it into self-destructing.

The results, announced yesterday, are heartening not just for people infected with HIV but also for the field of gene therapy, which remains highly experimental more than 20 years after scientists figured out how to use viruses to insert therapeutic genes into a cell's genome.

Mostly, the results are a big step forward for the biotech start-up that is developing the novel therapy and for its collaborators at the University of Pennsylvania.

"The buzzword in the field is viral 'fitness,' meaning how well the virus can replicate," said Gary McGarrity, executive vice president for scientific affairs at Virxsys Corp., in Gaithersburg, Md. "In eight of the nine patient samples we studied, we see diminished HIV fitness up to two years after treatment."

That raises the hope that even if medical science cannot come up with the Holy Grail of AIDS research - a vaccine to prevent HIV infection - patients may be able to keep HIV under control, perhaps without relying on the toxic drug cocktails that commuted what once was a death sentence.

"I think the Virxsys report is very important," said John Rossi, a molecular biologist at the City of Hope in California, who also is working on a gene-therapy treatment for HIV.

"A lot of HIV patients are over 60 now and they're suffering the consequences of these toxic drugs. This shows there are alternatives."

The field of gene therapy has suffered years of missteps and controversy - notably the 1999 death of Arizona teenager Jesse Gelsinger in an unrelated gene-therapy experiment at Penn.

"I think the field is really starting to accelerate," said physician Carl June, who leads the Penn team that is collaborating with Virxsys. "There was so much frustration for years. But now there are new breakthroughs."

The latest gene therapy, called VRX496, is still in early human testing intended to demonstrate safety and determine the best dosages.

Of the 54 patients who have been treated so far in the ongoing clinical trial, none have experienced serious side effects and many have seen clinical signs of effectiveness - their HIV viral loads have fallen and their supply of infection-fighting T cells has grown.

A Penn patient, one of the first and sickest to be treated, remains well more than four years later - even though conventional cocktails of anti-retroviral drugs had stopped working for him.

Yesterday's report, presented by Virxsys at a conference in Boston, looked deep into the molecular level of blood samples from nine randomly chosen patients to see whether the therapy was actually hitting its target.

VRX496 capitalizes on the fact that viruses are impotent on their own but powerful inside a cell. That is the only place they can replicate, by hijacking the host's molecular machinery. HIV seizes control by splicing its own genes into the DNA of infection-fighting T cells, the backbone of the immune system.

The genetic wizardry involved in outwitting HIV is complex. First, the researchers remove T cells from an HIV patient and insert into those cells a gene that stops the AIDS virus from reproducing. Then, using Penn's patented technology, the T cells are multiplied a hundredfold and put back into the patient.

The vehicle, or "vector," that is used to insert this protective gene into the T cells is novel in itself: a disarmed version of HIV.

The gene carries instructions that eliminate the AIDS virus' ability to wrap its DNA in an armored shell. So when HIV invades the T cell, it steals this new armor-making gene, escapes from the cell - and then finds itself unable to make the shield it needs to break into more cells.

The latest study also found that the inserted gene is a double-whammy for HIV. The virus tries to simply delete the gene - its favorite mutating tactic for becoming resistant to current drugs - but that, too, reduces its reproductive "fitness." (It gets "wimpy," to use June's word.)

The researchers found that blood samples from the nine cases presented yesterday were in fact loaded with the virus, most of it having mutated into harmless forms.

"For HIV to mutate around our treatment, it has to commit suicide," said McGarrity, the Virxsys executive.

If this gene therapy becomes an approved treatment, still years away, the estimated cost for the one-time series of infusions would be $130,000, said Riku Rautsola, Virxsys' chief executive officer. While that's a hefty sum, the lifetime cost for conventional HIV-fighting drugs is about $700,000.

"We hope [VRX496] will become a frontline therapy once we have proven the impact is durable," Rautsola said. "This would clearly be better in terms of quality of life for the patients."