

Faced with the continued failure of HIV-targeting microbicides, scientists have devised a radically different approach to preventing transmission of the killer virus: ignoring it.

Instead of aiming at the virus itself, they’re focusing on the body’s response to HIV’s initial attack. By muting distress signals sent by HIV’s first cellular victims, researchers hope to prevent the white blood cells on which HIV preys from responding and becoming infected themselves.

This cutting-fuel-to-the-fire approach is highly experimental, and has only been tried with a single compound. But it prevented infection in four of five macaque monkeys exposed to a close relative of HIV, signifying a potentially new direction in the fruitless search for a microbicide.

"If you can break one of the links in that chain, you can break the influx of target cells the virus needs," said University of Minnesota microbiologist Ashley Haase, co-developer of the new microbicide, described Wednesday in Nature.

The science is still uncertain, but so is the entire field of anti-HIV

microbicides. Hundreds of millions of dollars and thousands of researchers have yet to produce a substance that, when applied before sex, can reliably prevent transmission of a virus that kills nearly 3 million people every year.

A growing number of scientists think the progression of the disease is driven by inflammation. Previous research showed that exposure to

SIV — the simian equivalent of HIV — prompts the immune system to summon specialized white blood cells, which are the primary victims of both HIV and SIV. Once under attack, they call in more white blood cells. These also fall prey. The cycle repeats until infection is firmly entrenched.

"We’re trying to interfere with the host response on which the virus depends to establish infection," Haase said.



His team previously found that glycerol monolaurate, an FDA-approved antimicrobial compound normally used in soaps and other household products, dampened the inflammato ry response in cell cultures. Now they’ve shown the same effect in monkeys.



Whether human immune response to HIV parallels the monkeys’ response to SIV is unproven, but there are hints that it does: The same mechanisms can be observed in laboratory cultures of human cells, and high levels of vaginal inflammation are linked to higher HIV infection risks.

"Whether this particular drug would work in humans, nobody knows," said Leonid Margolis, a National Institutes of Health HIV researcher who was not involved in the study. But its significance, he said, resides less in these early tests than in signaling a conceptually new approach to microbicides.

Haase’s team made its microbicide from a mix of glycerol monolaurate and K-Y lubricating gel. After testing its basic safety on macaques, they treated five monkeys who were then exposed to SIV. Over the next two weeks, only one of the monkeys became infected. In an unprotected control group, all five monkeys became infected.

The microbicide didn’t appear to otherwise affect the monkeys, and left their vaginal bacterial flora — important to maintaining an environment hostile to infection — fully intact.

The macaques used by Haase’s are far from a perfect model for studying HIV treatments, but are considered useful for modeling the disease’s transmission. Still, said Haase, more and longer-term research is needed in monkeys before glycerol monolaurate can be tested in humans.

If it has even a small protective effect, "you could combine it with other approaches into a microbicide that targets several things the virus needs," said Haase. "Such an approach might be very effective — more effective than the components themselves might be."

Should glycerol monolaurate itself not work, some other inflammation-dampening compound might do the trick. "Inflammation is, in my mind, the engine that drives HIV infection," said Margolis.

Other scientists, however, warn against premature optimism.

Glycerol monolaurate also has surface-tension lowering properties in liquid, which could have directly inactivated the virus independent of any anti-inflammatory effects, said Robin Shattock, an HIV transmission specialist at St. George’s University of London and chair of the International Partnership for Microbicides.

Another surfactant microbicide candidate, nonoxynol-9, showed promise in monkeys but actually increased HIV transmission risk during clinical trials.

Even if glycerol monolaurate worked by reducing inflammation, said Shattock, it’s unclear whether it could sufficiently reduce real-world inflammation, which is often caused by multiple, sexually transmitted infections, of which HIV is only one.

"Only time will tell whether this is a major breakthrough, or if it is just another flash in the pan," he said.

Citation: "Glycerol monolaurate prevents mucosal SIV transmission."

By Qingsheng Li, Jacob D. Estes, Patrick M. Schlievert, Lijie Duan,

Amanda J. Brosnahan, Peter J. Southern, Cavan S. Reilly, Marnie L.

Peterson, Nancy Schultz-Darken, Kevin G. Brunner, Karla R. Nephew,

Stefan Pambuccian, Jeffrey D. Lifson, John V. Carlis & Ashley T.

Haase. Nature, Vol. 457 No. 7233, March 4, 2009.

Image by Ashley Haase

Abstract of viral progression from SIV contact to systemic infection in macaques. Green crosses signify clusters of infected cells at 4, 7 and 10 days following exposure.



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