BioWorld International Correspondent

LONDON - It might be possible to prevent male to female transmission of the human immunodeficiency virus by applying a drug to the vagina, a new study in macaque monkeys suggests. The findings also support a hypothesis on which receptor HIV uses to enter cells.

Robin Offord, professor of structural biology and bioinformatics at the University Medical Centre in Geneva, told BioWorld International: "This is the first time, as far as we are aware, that a biological molecule has succeeded in protecting all members of a group of monkeys that had been exposed to the virus. This is very good news."

The team - which includes collaborators Michael Lederman, of Case Western Reserve University in Cleveland; Ronald Veazey at Tulane National Primate Research Center in Louisiana; and Oliver Hartley, also from Geneva - showed that all five monkeys receiving the highest dose of the drug were protected from challenge with an engineered strain of the virus.

Trials in humans to establish the safety of the drug are planned.

A paper reporting the study appeared in the current edition of Science. Its title is "Prevention of Vaginal SHIV Transmission in Rhesus Macaques Through Inhibition of CCR5."

Offord is a co-founder of Gryphon Pharmaceuticals, of South San Francisco, and a paid consultant of the company. He first began studying molecules that could block the CCR5 receptor almost 10 years ago, when collaborating with the then Glaxo Wellcome Research Institute in Geneva on ways to control unwanted inflammatory reactions. He particularly was interested in a chemokine - a protein that helps mobilize white blood cells toward sites of inflammation - called RANTES.

One of the Glaxo staff cloned the gene for RANTES and expressed it in a bacterial-expression system. To her surprise, the cloned protein, called Met-RANTES, which had a modified amino terminus, turned out to be an antagonist of RANTES and incapable of stimulating the CCR5 receptor. Offord designed and made an improved version, called AOP-RANTES.

"This molecule was a quite decent inhibitor of inflammatory processes," Offord said. "We could have pursued this further, but around that time others discovered that CCR5 is used as a co-receptor to enable HIV to get into cells."

Seven years ago, they went on to show that AOP-RANTES was a "very potent" inhibitor of HIV infection in vitro. Since then, Offord, together with Hartley, has designed and made a whole series of variants on the original structure of AOP-RANTES, with a view to enhancing the molecule's activity still further.

The work reported in Science featured one of those modified molecules, called PSC-RANTES.

The macaques first were treated with progesterone, a hormone that thins the vaginal wall and facilitates infection. The researchers then split the 30 animals into six groups of five, anesthetized them and treated them intravaginally with one of five concentrations of PSC-RANTES or saline placebo.

Fifteen minutes later, the monkeys were given a dose into the vagina of a hybrid virus called SHIV, which contains the inner parts of the simian immunodeficiency virus and the outer parts of HIV.

The highest dose of PSC-RANTES protected all five recipients from SHIV infection. The second-highest dose protected four out of five monkeys treated, and the third highest protected three of five animals.

Overall, 12 of 15 animals pretreated with more than a 100-micromolar dose were protected from infection, compared to only four of 15 animals pretreated with less than a 100-micromolar dose or placebo (p=0.009).

The study appeared to lay to rest a controversy as to whether it is enough to target CCR5 to protect from infection or whether it might be necessary to target other receptors as well.

"Our molecule will only block CCR5, so for all the animals in the top-dose group to be protected, this means that all you have to do is to hit that one target and you have what is commonly called a microbicide," Offord said.

"Unfortunately, the cost of the dose required in this study would put it out of the reach of most people in the countries where such a preparation is so urgently needed," he said. "But we are now working on both reducing the dose required in vivo and enlisting the help of the biotechnology industry to use existing technology to bring the cost of production down."

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