San Francisco Chronicle - The Voice of the West, San Francisco, CA 94119 - 17 Nov 1995
Charles Petit, Chronicle Science Writer

Despite their very preliminary nature, the test results were given prominent play in today's issue of Science magazine, a leading research journal. They follow a series of recent reports that are raising hope among AIDS researchers that, after years of frustration and drift, the search for effective drugs is making some headway.

"I am becoming much more optimistic now than I was just two years ago," said Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology, operated by the University of California at San Francisco at San Francisco General Hospital. "There are some striking changes (in research). I am seeing more examples of natural resistance to HIV, and we are seeing more promising therapeutics that target different parts of the life cycle of the virus."

The first of today's reports describes an experimental drug called PMPA that was injected into 25 macaque monkeys up to 24 hours after they were given large injections of SIV, or simian immunodeficiency virus. The organism closely resembles human immunodeficiency virus, or HIV, and causes a disease similar to AIDS in monkeys. Daily PMPA treatment continued for four weeks after researchers injected the virus into the animals.

The virus doses were 10 times bigger than ordinarily needed to cause infection. Yet none of the monkeys developed any sign of infection. Exhaustive tests failed to find any trace of the virus in the treated animals more than a year after the experiments began. The monkeys also had no apparent side effects.

"Such complete protection with no toxicity is unprecedented in the monkey model of AIDS," said Dr. Anthony S. Fauci, director of the federally operated National Institute of Allergy and Infectious Diseases, which sponsored the study.

The most popular anti-HIV drug now available, AZT, prevents infection under such circumstances less than 6 percent of the time. PMPA attacks the same part of the virus machinery, a substance called reverse transcriptase, as AZT does but has a different chemical structure.

The substance is made by Gilead Sciences of Foster City; the research on it was conducted by Che-Chung Tsai, a pathologist at the University of Washington Regional Primate Research Center in Seattle. Further tests will explore how well monkeys tolerate high doses of the drug. If those tests go well, human tests will follow.

Tsai said he delayed publishing for a year because results of the first trials "were so good we could not believe them." He said the drug is by far the most powerful antiviral compound his lab has tested.

The drug tested on monkeys, researchers cautioned, has not been shown to be helpful for animals in which infections are well established. So far, it works only if given immediately before or after the animals are exposed.

But scientists hope it could lead them to a medication for people just exposed to the virus. And some day, it may make a "morning after" pill possible.

A spokesman for Gilead said no timetable has been set for human experiments, but Greene at the San Francisco institute said, "This is very intriguing. I expect it will be pedal to the metal to get toward human tests."

Although PMPA seems to work well if given when an infection starts, many researchers fear that in cases where infection is well established, HIV would rapidly develop resistance to it.

The other report being published today offers hope for a drug against which the virus cannot find a defense.

The drug, part of a class of substances called DIBAs, destroys microscopic features on the AIDS virus, called zinc fingers. Unlike other proteins on the outer coating of the virus, the zinc compounds do not undergo mutation.

"If the virus changes the zinc finger, it dies. It would commit suicide," said the report's lead author, Dr. William G. Rice, director of the Laboratory of Antivrial Drug Mechanisms at the National Cancer Institute in Maryland. The tiny protuberances are necessary for the virus to translate its internal genetic code into forms that can be inserted into human cells, and also for the assembly of new viruses from raw materials inside infected cells.

In culture tests, one form of DIBA completely stopped the spread of HIV in laboratory cell lines, both killing the viruses floating free in the fluid between cells and preventing infected cells from serving as factories for production of new viruses. Several other teams and companies, including Octamer Corp. in Marin County, are also at work trying to find safe, effective substances that dissolve the zinc fingers off the virus.

Rice said it is too soon to be confident that the drugs that work against zinc fingers so well in glass dishes will be safe or effective in people. But he added, "I head the laboratory where all the compounds that come to (the National Cancer Institute) are screened, thousands of them. We have lots of inhibitors for lots of things that HIV does, and this is by far the best."

Copyright (c) 1995/San Francisco Chronicle. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Permissions Desk, San Francisco Chronicle, San Francisco, CA.

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