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Researchers harness virus to create new HIV drugs

By Wai Lang Chu , 29-Aug-2005

A harmless virus could hold the key to the production of a more effective HIV drug after researchers employed this virus in ongoing studies. The research aims to outmanoeuvre the mutating nature of the HIV virus, which has become skillful at developing resistance to broad-spectrum methods.

The study aims to overcome the problem of why some strains of HIV are naturally resistant to the presence of such drugs. That is why treatment with monotherapy (a single antiretroviral drug) is destined to fail.

In addition, up to 20 per cent of new infections now involve the transmission of resistant virus, meaning new classes of HIV drugs (especially against novel targets) will provide the only hope of treatment for an increasing number of patients.

Researchers from the University of California employed a viral bacteriophage to learn how a HIV protein could respond to a new class of anti-viral molecules they had previously discovered.

By constantly mutating into new variations, HIV, in particular, has become very skilled at developing resistance to broad-spectrum methods to inhibit its expansion. Because of this, the development of effective HIV drugs has become difficult and expensive.

Gregory Weiss, an assistant professor of chemistry and molecular biology and biochemistry and Allison Olszewski, a fourth-year graduate student in the Weiss laboratory, found that the bacteriophage could model millions of different mutational variants of an HIV protein called Nef.

Knowing how the entire population of Nef variants responds to new drugs gives researchers greater ability to identify broad-spectrum, anti-HIV compounds. This approach, Weiss said, can make drug discovery efforts for other anti-viral therapies faster and more effective.

"Viruses are clever about mutating to defeat the best efforts of chemists and biologists," said Weiss,

"By recruiting a harmless virus, we're learning how HIV will respond to new classes of anti-viral drugs before these compounds are tested in the clinic, which is currently an expensive and time-consuming process," he added.

The Weiss laboratory specialises in developing massive libraries of proteins that can potentially target and bind to other proteins, using a process called phage display. In this study, Weiss and Olszewski first created one such library by attaching the Nef protein onto the bacteriophage, which was then coaxed into synthesizing the millions of mutational variants of Nef.

The researchers then targeted this library, which they call an allelome, with a second library of small-molecule compounds in order to identify the specific compounds that could target the entire population of Nef mutational variants. The results suggest chemically simpler, more flexible compounds could better accommodate viral mutations.

The study results appear in the online version of the Journal of the American Chemical Society.