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Ferreting Out HIV

Compound that pulls the virus out of hiding is synthesized

by Sarah Everts
May 5, 2008 | A version of this story appeared in Volume 86, Issue 18

ANTIRETROVIRAL THERAPY knocks HIV down to undetectable levels in infected patients, but reservoirs of the virus concealed in immune cells prevent its complete eradication by current treatments.

Now, a new and straightforward synthesis of a natural product that can pull latent HIV out of hibernation paves the way for clinical development of a treatment that could completely flush out the virus from patients.

Chemist Paul A. Wender and his colleagues at Stanford University built prostratin, which originates from the South Pacific tree Homalanthus nutans, from a commercially available phorbol feedstock in five steps (Science 2008, 320, 649).

The flexible synthesis permits replacement of prostratin's acetyl group and other modifications, thereby "opening access to a variety of new analogs," Wender says.

"It's fantastic to have not only a practical synthesis of prostratin but also a simple one," says biologist Paul A. Cox, director of the Institute of Ethnomedicine, who learned of prostratin's antiviral activity from Samoan healers in 1984 and introduced the compound to Western scientists. "But this is more than a nice synthesis; it could change the trajectory of HIV drug development."

Credit: Paul A. Cox
Prostratin, found in the Samoan H. nutans tree (shown), can be synthesized from phorbol.
Credit: Paul A. Cox
Prostratin, found in the Samoan H. nutans tree (shown), can be synthesized from phorbol.

One of HIV's more frustrating characteristics is that it takes up residence in immune T-cells, "creating a latent HIV reservoir that doesn't go away" because existing antiretrovirals can't reach it, notes Robert F. Siliciano, an immunologist at Johns Hopkins University School of Medicine. Even when HIV can't be detected in the plasma, it's still holed up in the T-cells.

These viral reservoirs mean HIV patients must stay on antiretroviral treatment indefinitely, a hefty expense for the 33.2 million people currently living with HIV, most of whom live in sub-Saharan Africa.

In the 1990s, Cox and collaborators found that prostratin can coax HIV out of hiding in T-cells, which could, in principle, allow existing antiretrovirals to completely rid the body of the virus.

But the only source of prostratin was the Samoan forest. Extracting the natural product would be too expensive and too environmentally taxing if the compound were to become a drug.

A remaining challenge faced by prostratin proponents is that its kick is also its Achilles heel, Siliciano notes. The compound pulls HIV out of hiding by activating immune system T-cells, which could have inflammatory and other side effects, he says.

Ideally, the simple synthesis will permit the development of analogs that can address such side effects as well as efficacy issues, Cox says. Should an analog reach the market, he adds, "I hope that the intellectual heritage of prostratin, which began with Samoan healers, will be recognized by the negotiation of a fair and equitable return with the Samoan people."



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