San Francisco Chronicle - The Voice of the West, 901 Mission Street, San Francisco, CA 94119 - Friday, November 14, 1997 - Page A1
David Perlman, Chronicle Science Editor

The finding provides both a warning and a promise for many AIDS patients who have seen their disease symptoms vanish after therapy with powerful new drug combinations.

The warning: The difficult and costly new treatments must continue indefinitely, the experts say, noting that the AIDS virus seems capable of lying in wait for years, fully capable of emerging anytime the patient stops taking the antiviral drugs.

The promise: Patients who are benefiting from the drug combinations may remain free of debilitating illness as long as they continue their treatment. There is also no evidence that the newfound reservoirs of hidden, inactive virus have developed any resistance to the drugs.

The discovery also underscores an urgent need for new AIDS drugs aimed at more vulnerable targets within the interior of the virus.

What's needed is a weapon capable of mounting a final attack on the stubborn viral reservoirs, said Dr. Anthony Fauci, the government's chief AIDS researcher, who heads the National Institute of Allergy and Infectious Diseases.

Fauci and other scientists in his laboratory are one of the three teams that have detected HIV hidden within the most important white blood cells of the immune system, known as CD4 cells. Another group is headed by Dr. Douglas D. Richman at the University of California at San Diego, and the third is led by Dr. Robert F. Siliciano at Johns Hopkins University in Baltimore and Dr. David D. Ho at the Aaron Diamond AIDS Research Center in New York.

Reports by the Richman and Siliciano teams are being published today in the journal Science, while the Fauci group's findings will be published later this month in the Proceedings of the National Academy of Sciences.

The three research groups have studied 41 AIDS patients, all but three of whom have been on combination AIDS-drug therapy for up to 2 1/2 years. The drugs include one or more of the relatively new compounds called protease inhibitors, plus at least two of the more traditional AIDS medicines known as nucleoside analogues, which include AZT, 3TC, d4T or ddi.

The protease inhibitors became widely available more than two years ago. Many patients who use the new drug combinations rigorously on a rigid, expensive and extremely taxing 24-hour-a-day schedule have seen the load of HIV in their bodies vanish to undetectable levels.

And because so many desperately ill and disabled AIDS patients apparently have returned to full health under the drug regime, some have even hoped that they were cured and their cumbersome therapy -- costing up to $20,000 a year -- could stop.

Many AIDS researchers also have raised the possibility that the new therapies would wipe out the virus completely, thereby offering a genuine cure for AIDS. Some researchers have even proposed trying to see if patients who volunteered would continue to thrive after the drug combinations were withdrawn.

The new discovery ends that idea, but it also helps scientists understand the targets they must still defeat.

"Clearly, this has major implications for our prospects of eradicating HIV," Richman said. "But we now know what we're contending with. Either we have to figure out how to eliminate this reservoir of virus, or continue suppressive therapy indefinitely."

That will mean finding a vulnerable new region in the interior of the virus that drugs have not yet probed -- probably one of the several enzymes that the virus must use in order to reproduce, Fauci said.

Although the hidden viruses that the researchers have discovered are inactive and do not reproduce, they are fully capable of replicating once they emerge from the CD4 cells in which they lurk, the scientists found.

Most CD4 cells infected with HIV produce many copies of the virus before dying. But some of those infected cells become inactive and enter a "resting state." During that resting state the infected cells do not produce copies of the virus, but they remain a reservoir for small numbers of latent virus, the scientists now know. Those latent viruses, however, are fully competent to start reproducing again and to renew their assault on the immune system, according to the researchers.

Until now, Fauci said, scientists had assumed virus particles remaining in cells after treatment with the drug combinations were dead and incapable of returning to activity.

Now, however, genes for creating new and reproducible virus have been detected in the resting CD4 cells after treatment with the drug combinations for up to 30 months, according to the Siliciano group.

And if the aggressive therapy is stopped too soon, it could mean that a patient's immune system -- still weakened despite its initial recovery as a result of the drug treatment -- would be unable to resist a new wave of reproducing viruses, Fauci said.

The wily virus is known to mutate frequently under the attack of most of the older AIDS drugs, and drug resistance has become a major fear for people with AIDS. That fear has not become a reality, and even the hidden viruses show no sign that they have become resistant to the drug combinations, the scientists said.
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