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Drug Leaves HIV Defenseless

WWW- A REVOLUTIONARY drug that could help overcome HIV’s growing resistance to existing antiviral drugs is about to be tested in combination with standard antivirals. Called PA-457, it is the first of a new class of anti-HIV compounds called maturation inhibitors. The drug is still in its early stages, and will not be generally available for at least three years.

Up to 80 per cent of HIV-positive people on treatment show resistance to one or more of their drugs, according to Graham Allaway of Panacos Pharmaceuticals in Gaithersburg, Maryland, which is developing PA-457. Panacos hopes to begin trials this month to test how well the drug works in patients whose existing drug regimes are failing.

PA-457 aims to overcome this resistance by attacking HIV on a new front. Many existing drugs work by blocking reverse transcriptase, an enzyme that enables HIV to replicate within a cell. Others disable protease, which helps to assemble the virus into particles that infect other cells.

Recent experiments in collaboration with Michael Sakalian and his colleagues at the University of Oklahoma Health Sciences Center in Oklahoma City have shown that PA-457 works in a different way. It attacks HIV by disrupting formation of a conical shield, called the capsid protein, which stores and protects the RNA heart of the HIV particles as they bud out from infected cells.

The latest research, in which the virus was examined under a microscope, shows that the drug binds to the capsid protein at a crucial stage in its manufacture (Journal of Virology, vol 80, p 5716). Normally, the capsid protein is clipped apart from a major structural protein called the gag protein, and is then assembled into a cone. PA-457 stops it being clipped off, causing it to form a leaky sphere that leaves the core RNA exposed (see Diagram). This cripples the virus, preventing it from infecting any other cells once it buds out from the host.

Previous lab experiments on infected human cells have shown that the drug defeats strains of HIV which are resistant to other anti-HIV drugs. A small human trial of the drug, reported last August, showed that when given on its own it rapidly clears most HIV from the blood, driving down the levels tenfold in a matter of hours.

The trial planned for this month is intended to discover how the drug performs as part of a combination treatment with other anti-HIV drugs, which is a more realistic situation. Forty-eight patients whose existing drug regimes are failing will receive either PA-457 or a placebo in addition to their standard drugs. There are plans to try the drug along with new regimes tailored to individual patients, though Allaway warns that larger trials are needed and PA-457 will not reach the market until 2009 at the earliest.

Other HIV researchers are also enthusiastic about PA-457. “It’s a truly novel new class of drugs, and I really support their development,” says Charles Boucher of the University Hospital Utrecht in the Netherlands. “If [PA-457] turns out to be non-toxic, easy to use and not to select for resistance, it will find good use,” he says.

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