San Francisco Examiner - Monday, January 4, 1999
Ulysses Torassa, Examiner Medical Writer

That seemingly basic aspect of the disease remained unknown for years and has only been shown definitively by the work of investigators at the Gladstone Institute of Virology and Immunology at UC-San Francisco. They tagged newly produced immune cells in uninfected people and showed that the rate of production of the so-called T-cells fell dramatically in people who had active virus in their bodies.

The outcome "is a significant change in our understanding of how HIV affects the immune system," and could lead to new avenues for future therapies, said Warner Greene, director of the Gladstone Institute.

The team's results are to be carried in the January issue of Nature Medicine, which also is publishing research by two other teams who have found promising techniques that could some day lead to better ways to treat HIV infection.

The San Francisco work, on top of past studies, puts to rest four years of debate within the AIDS research community over whether HIV acts primarily by destroying T-cells or by keeping them from being produced in the first place, according to Swiss scientist Giuseppe Pantaleo. Since 1995, researchers have suspected that HIV was wreaking havoc on the body by doing more than simply destroying T-cells, and the resulting controversy has at times been harsh, Pantaleo wrote in a companion article in Nature Medicine. The study focused on 21 patients, some receiving powerful anti-retroviral therapies, others untreated and another group that was HIV-negative.

In the group whose infection was held in check by the drugs, the rate of new cell production increased dramatically, which was the main reason why their immune cell counts rose.

It's not entirely clear how the virus derails T-cell production. But Joseph M. McCune, the study's senior investigator, said one possible explanation is that it interferes with the work of the bone marrow and thymus, where T-cells are produced.

Also, he said HIV could be keeping so-called memory T-cells from dividing and living on. Those are the cells that have learned to recognize invaders from previous battles with various infectious agents. They and their offspring retain the memory of the invader and can marshal a response when it reappears.

The insight already suggests new ways of combatting AIDS - namely by rebuilding the T-cell production line, McCune and Greene said. That could involve cytokines, a large class of immune system molecules that are known to be key in the creation of immune cells, Greene said.

Any advances in rebuilding immune function could also someday be used by cancer patients, whose ability to fight off disease is temporarily destroyed by chemotherapy, McCune said.

In the two other studies published Tuesday, researchers say they have come up with two techniques that could be used to combat HIV in novel ways.

One uses a specially engineered "Trojan Horse" protein that can insert itself into cells and interact with parts of the HIV virus to turn on the cell's own suicide mechanism. That causes infected cells to die off, said Steven F. Dowdy, a Howard Hughes Medical Institute investigator at Washington University in St. Louis.

The technique holds promise for the increasingly number of people expected to be infected with strains of HIV that are becoming resistant to the powerful protease inhibitors and anti-retroviral drugs now widely used.

The work has only been done with cells in the lab, but Dowdy said the concept appears sound and a company in La Jolla is already working on clinical applications. He said they are just now moving into animal testing.

If it works, the concept could be used in other infectious diseases like hepatitis C and malaria, where there are now very few effective treatments, Dowdy said. He also said he thinks it could have applications for killing cancer.

Greene said he was impressed with Dowdy's work, calling his ability to get cells to take up the giant proteins a great feat of "molecular gymnastics." But he also cautioned that any therapy that resulted might be hard to administer.

Another research team, at the University of Washington in Seattle, announced success with a technique in which they injected a small number of patients with so-called killer T-cells meant to wipe out HIV. They showed that the cells migrated to the lymph nodes and killed HIV-infected cells.

Greene said the technique was interesting, but it is unlikely that type of therapy would be practical on a large scale in industrialized countries like the United States, much less in developing nations where the disease is spreading most rapidly.
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