Wall Street Journal - September 28, 2000
Mark Schoofs

The approach of the new study, which aims to "train" patients' immune systems to fight HIV without drugs, looks like it won't be enough for most of those with longer-term infections, says Bernard Hirschel of University Hospital and Medical School in Geneva, who is running the largest trial of this approach in long-term patients. In preliminary results, he found that only three of 43 patients were able to hold the virus to very low levels after going on and off drugs several times.

Nowhere is the distinction between long-term and recent infection made clearer than in a pair of studies conducted on monkeys by Franco Lori, director of the Research Institute for Genetic and Human Therapy in Baltimore. In monkeys treated right after they were infected, Dr. Lori's team was able to induce powerful immune control of the virus after four cycles of starting and then stopping treatment. But in a similar study of monkeys that had progressed to AIDS before treatment cycles were initiated, not one was able to achieve comparable immune control.

One danger of starting and stopping drug therapy: It might induce drug resistance. When patients are off drugs, HIV mutates extremely rapidly, creating multiple strains in a patient's body. "That makes it harder for the immune system to control the virus," explains Bruce Walker of Massachusetts General Hospital, who led the team that published Thursday's study, "because it's not dealing with one enemy, but with 10 or 100."

So various researchers are trying what should be a safer approach: injecting long-term patients who are on standard AIDS drug cocktails with experimental HIV vaccines. Those experimental vaccines include Aventis Pasteur's Alvac, which hitches HIV genes onto a canary virus that doesn't cause disease in humans, and Immune Response Corp.'s vaccine made from killed HIV and developed by Jonas Salk.

Many researchers are skeptical that these vaccines are powerful enough to make a person's immune system control HIV. "Nobody's had a good vaccine yet," says Douglas Richman, a veteran HIV researcher at the University of California at San Diego. Dr. Richman says he holds out hope for a Merck & Co. vaccine that is still in very early trials.

Meanwhile, some scientists are tackling the problem from an entirely different angle. Clifford Lane, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., is focusing on a natural chemical in the body, called interleukin-2, that makes cells reproduce. Dr. Lane hopes that patients can one day take a standard drug cocktail in conjunction with interleukin-2 to increase the number of key immune-system cells. Patients could then stop their medicine. When the number of these cells drops again, they would go back on interleukin-2 and the drugs. Theoretically, this could not only keep the immune system functioning at an adequate -- though diminished -- level, but could also spare patients the side effects of constantly taking drugs.

But beyond just maintaining immune function at some reduced level, could the immune systems of long-term patients be fully regenerated? That may depend on whether patients still have an active thymus, the organ in the chest that produces T-cells. (The name "T-cell" is short for thymus-derived cells.) Previously, it was thought that the thymus stopped functioning in adults, but studies have shown that the thymus continues to function in many HIV patients. At the frontiers of immunology, scientists are struggling to figure out how to turbocharge fresh T-cells emerging from the thymus.

Some researchers, such as Dr. Lane, who collaborated with the gene-therapy firm Cell Genesys Inc. of Foster City, Calif., have tried taking T-cells out of patients, genetically altering them so that they will seek out and attack HIV, and then injecting these cells back into people. The studies have shown that the cells can survive, but whether they can fight HIV is less clear.

Some researchers are even trying to use HIV against itself. Didier Trono of the University of Geneva, Switzerland, wants to insert new genes into immune-system cells to make them resistant to HIV. But how to get the genes into the cell? A common method is to load the genes onto some sort of benign virus and let that virus carry the new genes into the cell, like a truck carrying cargo. Dr. Trono's radical idea is to use HIV itself as the delivery vehicle -- precisely because it's so effective at inserting itself into immune cells.

A key obstacle, of course, is that HIV happens to be one of the most lethal viruses in history. But Dr. Trono says he and others in the field have managed to remove the disease-causing elements of the virus. "It's like a car that is left with only the steering wheel and the tires," he says, though he concedes safety problems remain.

Even if these experimental efforts succeed -- which is by no means assured -- they would likely be expensive to implement. They would also probably require high-tech facilities that are lacking in Africa and other areas where AIDS is at its worst. But, says Dr. Walker, "when we have an approach that works, then we can make it cheap."
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