AIDSWEEKLY Plus; Monday, September 7 & 14, 1998
Daniel J. DeNoon, Senior Editor

Gallo warned that even though they represent immense progress, current AIDS therapies are not good enough. He urged researchers and policymakers to prioritize the search for better and less toxic AIDS therapies.

"The problem isn't solved: we need newer and better and less toxic drugs," he said in his plenary presentation to the 12th World AIDS Conference, held June 28-July 3, 1998, in Geneva, Switzerland. "It is too early to put all our efforts into the development of preventive vaccines."

In a later press conference, Gallo emphasized that he does not mean vaccine research should be abandoned.

"Obviously I think the vaccine effort is important: a fourth of our institute is working on a vaccine," said the head of the Institute for Human Virology, Baltimore, Maryland. "But even if we had a vaccine tomorrow, by the time it was deployed we'd have many more infected people we need to treat."

Gallo suggested that the best time to attack the AIDS virus is during the earliest stages of its life cycle, when it binds and enters target cells. He called attention to two novel approaches to this problem.

The first approach is to prevent the virus from changing into the conformation needed for cell fusion. This is the extraordinary promise of the new drug pentafuside or T-20, under development by Trimeris Inc., Durham, North Carolina. The small-peptide drug attaches to the gp41 transmembrane protein of HIV, which the virus must properly deploy during cell fusion. When T-20 binds to HIV - at a site very well conserved for all HIV-1 strains - it acts as a monkey wrench in the gears of the virus's cell-entry mechanism.

Early clinical trials of the drug, under the auspices of Michael Saag at the University of Alabama, Birmingham, show that the T-20 is safe. The short serum half-life and pharmacokinetics of the current formulation require administration via a portable infusion device, but results have been spectacular in the few patients treated thus far: antiviral action equivalent to protease inhibitors and no apparent toxicity. Moreover, resistance to the drug develops slowly in vitro; no cross resistance to existing HIV drugs is seen.

The second approach highlighted by Gallo is the use of chemokines or chemokine-like drugs to down-regulate the receptors HIV uses for cell entry.

Gallo pointed to recent studies showing that the anti-HIV action of beta chemokines depends on down-regulation of chemokine receptors rather than simple blocking of the HIV docking site.

Moreover, Gallo announced new findings suggesting that glycosylaminoglycans play an important role in the virus/cell fusogenic event. These small sugar molecules are closely associated with chemokine receptors but do not penetrate the cell surface.

"Glycosylaminoglycan binding is a key determinant for the antiviral effect of chemokines," Gallo said. "This is going to be very important."

He said that low-level expression of the CCR5 chemokine receptor that mediates most HIV infections is associated with protection from infection in epidemiologic and primate studies.

"And how do you get low CCR5 expression? By making high levels of beta chemokines," Gallo said. "We'd like to regard beta chemokines as the first-line defense against HIV infection."

Never one to avoid a controversy, Gallo challenged the "tap-and- drain" model of HIV pathogenesis famously put forward by David Ho of New York's Aaron Diamond AIDS Research Center. This model holds that a constant supply of T cells (the tap) is infected and killed by HIV (the drain) in an intense and ongoing process.

But Gallo suggested that the majority of as-yet-uninfected T cells don't proliferate properly in HIV infected people.

"This works against the tap-and-drain model," he said.

This defect in T-cell proliferation appears to be caused by free Tat protein excreted by HIV, and by the overproduction of alpha interferon first reported in HIV infected patients by New York physician Joseph Sonnabend.

Gallo therefore suggested vaccination against Tat - and against alpha interferon. He said that preliminary data from pilot trials of this approach are "of great interest." These trials are being conducted by French researcher Daniel Zagury with Gallo's support.
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