Nov. 9, 2001 In the lab, prostratin leads a double life. On the one hand, it can prevent the AIDS virus, HIV, from infecting cells. At the same time, it exacerbates virus growth in cells already infected.
Researchers at Jefferson Medical College are hoping to take advantage of prostratin's alter ego. They've come up with a strategy they think can be used to flush HIV out of its cellular hiding places and into the waiting grasp of powerful drugs and the body's immune system. If they're right, says Roger J. Pomerantz, M.D., professor of medicine, biochemistry and molecular pharmacology and chief of the division of infectious diseases at Jefferson Medical College of Thomas Jefferson University in Philadelphia, they may someday be able to eradicate HIV from the body.
In the last five years, a cocktail of powerful anti-HIV drugs called highly active antiretroviral therapy (HAART) has in many cases made AIDS a chronic, manageable disease. But HAART is not a cure. The virus goes into hiding, plummeting to undetectable levels in the blood, lying dormant in so-called cellular reservoirs. Now, Dr. Pomerantz, who is also director of the Center for Human Virology at Jefferson Medical College and who led the work along with Joseph Kulkosky, Ph.D., assistant professor of medicine at Jefferson Medical College, and colleagues at the National Cancer Institute in Bethesda, Maryland, have demonstrated in the laboratory that prostratin, a natural compound that comes from a Samoan tree, can stimulate the two main hiding areas in patients with HIV infection who are taking HAART, namely two types of cells in the immune system, the CD4+ T-lymphocyte and the macrophage. The work shows that in cells obtained from patients on HAART, virus can be driven out of its reservoirs, possibly leading to death of the virus from the anti-viral drugs. The scientists report their work November 15, 2001 in the journal Blood.
"What's nice about this is that it is really a second generation approach," Dr. Pomerantz says. "We and a few other groups have trials going on - we're the only locally, maybe one of two in the country using first generation FDA-approved compounds to try to stimulate HIV out of latency as well as decreasing virus replication. Prostratin would hopefully be a second-generation drug that might be more successful.
"Using prostratin may be a kinder, easier way to give stimulation - it doesn't stimulate quite so much," he explains. "Also, this may be the first drug that might stimulate both T-cells and macrophages, both of which could be reservoirs for virus." Other drugs are used to stimulate the virus but are toxic, he says. "We would like to see something that is less toxic. Prostratin is a nice candidate because it targets the macrophage.
"Where do you go with this?" he asks. "It clearly works in the laboratory to stimulate HIV out of latency from patient cells who have no detectable virus in the blood." The next step, the researchers predict, will be to use prostratin on patients, perhaps within the next year.
In another trial testing the stimulation theory, he and his coworkers have been looking at a group of HIV-positive patients in the Delaware Valley whom had no detectable virus in the blood for one year after taking HAART. In the study, patients receive "intensification" and "stimulation" therapy. Dr. Pomerantz explains that stimulation drives HIV out of latency, enabling it to be able to be killed by drugs. Intensification is aimed at "shutting off that continuing low-level replication," he says, using several anti-HIV drugs, such as DDI, OKT3 and IL-2.
"It's a two-pronged approach, trying to stop replication and then drive out any latent virus so it can be killed," Dr. Pomerantz says.
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