For 20 years, AIDS researchers have searched for a vaginal microbicide that can block HIV, but they have made little progress. One gel has shown hints of working in a large-scale human study (ScienceNOW, 9 February), but the rest have failed or even caused harm. Now a new monkey study suggests that a microbicide containing a compound that many investigators would consider old-fashioned may have the power to thwart the AIDS virus.
The failure of first-generation microbicides has led the field to largely abandon the strategy behind them: that HIV could be stopped by compounds, such as soaps, that disable the virus without specifically attacking it. Today, most microbicides in human studies or on the drawing board contain anti-HIV drugs that cripple a critical viral enzyme. Yet as a team led by Ashley Haase of the University of Minnesota, Minneapolis, found, a nonspecific microbicide that targets the vaginal immune responses works remarkably well in monkeys.
Haase and co-workers first detailed how SIV, the monkey version of the AIDS virus, establishes a vaginal infection. By examining blood and vaginal tissues, the researchers found that SIV causes an inflammatory immune response, which recruits mobs of CD4 white blood cells--the virus's favorite target--to the site. If Haase and colleagues could prevent this from happening, they reasoned, they might be able to stomp out SIV's spark before it started a fire.
The researchers decided to test a microbicide that contains glycerol monolaurate (GML), a fatty acid that has proven safe in many products: It's used as a fiber finish in tampons and also as an emulsifier in many foods and cosmetics. Unlike soap-based microbicides, GML is not a so-called surfactant that aims to disrupt the viral membrane, says Haase. Rather, he was intrigued by its documented ability to dampen the immune responses triggered by vaginal epithelial cells when exposed to toxins.
After the microbicide showed promise in test-tube experiments, Haase's team moved on to rhesus macaques. They applied the GML gel daily for 6 months and showed that, as hoped, it reduced the inflammatory response in the vagina. The researchers then "challenged" five monkeys, placing SIV in their vaginas. Five other monkeys served as controls and received intravaginal gel without GML. Within 2 weeks of the challenge, the control monkeys developed high levels of the virus, whereas the GML-treated monkeys showed no signs of SIV infection. Haase and colleagues report their findings online today in Nature.
Experts are divided over the significance of the work. "I find the story quite compelling, and it's making me rethink some of the biases I have developed about moving forward with anything other than antiretrovirals," says Sharon Hillier, a reproductive infectious disease specialist at the University of Pittsburgh in Pennsylvania who heads the Microbicide Trials Network sponsored by the National Institute of Allergy and Infectious Diseases. But Robin Shattock, an immunologist at St. George's University of London who coordinates the European Enterprise network on vaccines and microbicides, notes that the study does not rule out the possibility that GML has surfactant activity against the AIDS virus, which would undermine the assertion that protection occurred because of a dampened immune response. "If this is just another surfactant, the paper is about 20 years out of date," he says. "If it's a new mechanism interfering with innate signaling, it's really quite exciting."
Haase concedes that the study does not rule out the possibility that GML inactivated the SIV, and he candidly notes that it has several other limitations, too. SIV recently surfaced in one of the treated monkeys that at first thwarted the challenge. He also notes that the monkeys received loads of GML prior to the challenge and that the team doesn't know how frequently women would have to use it to dampen the inflammatory response.
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