Published online 4 March 2009 | Nature | doi:10.1038/news.2009.135

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Microbicide protects monkeys from HIV-like virus

Gel may fight virus by suppressing counterproductive immune responses.

HIV virusA microbicide gel may have prevented some monkeys from contracting an HIV-like virus.Getty

A microbicide made from glycerol monolaurate — an ingredient in some foods and cosmetics — can protect female monkeys from contracting an HIV-like virus, researchers have found. The compound may act by suppressing an unfortunate immune response that helps the virus rather than fights it.

In a report published in Nature1, immunologist Ashley Haase of the University of Minnesota in Minneapolis and his colleagues propose a new approach to microbicide development. Other candidate microbicides cripple the virus itself, or its interactions with its favoured target — immune cells called CD4+ cells.

But while characterizing the earliest stages of infection, Haase and his colleagues found how and when the immune system recruits more CD4+ cells to the site of infection — a response that helps the virus to spread. Inhibiting this immune response, Haase reasoned, could stop the virus in its tracks.

"It is a new idea and sort of counterintuitive," says Haase. "You would think we should induce the innate immune response. But it turns out these viruses have not only learned to live with that immune response, they relish it."

“It turns out these viruses have not only learned to live with that immune response, they relish it.”

Ashley Haase
University of Minnesota

The results could provide a further boost for the field of HIV microbicides. In February, preliminary results from a clinical trial of the candidate microbicide Pro 2000 suggested that the gel reduced HIV infection in women who used it (see 'Microbicide gel may help against HIV'). But although the results were promising, they were not statistically significant, leaving researchers to wait on findings from a larger trial due later this year.

Nevertheless, that flash of hope might have stimulated renewed investment in the field: soon afterwards, the Bill & Melinda Gates Foundation and the UK Department for International Development together awarded nearly US$130 million for microbicide development.

Counterproductive countermeasures

The early stages of HIV infection are difficult to study in humans, because the time of initial infection is often not known. So Haase and his colleagues looked at a related virus — called simian immunodeficiency virus (SIV) — in female rhesus macaques (Macaca mulatta). The researchers monitored the small population of CD4+ cells that are initially infected in the cervix and vagina, then watched as more of these cells arrived and expanded the site of infection.

The team also found that the immune system generated several proteins during the first few days of infection. These proteins, the chemokines MIP-1α, MIP-1b, and Mip-3α, have previously been shown to attract CD4+ cells.

This finding reminded Haase of work done by a fellow immunologist at the University of Minnesota, Patrick Schlievert. Schlievert's lab had found that glycerol monolaurate inhibits the production of some deadly bacterial toxins, including anthrax toxin and toxins responsible for toxic shock syndrome. The compound also inhibits some immune responses to a toxic shock syndrome toxin2.

So Haase mixed glycerol monolaurate with a gel, and tested its ability to block SIV infection in the macaques. Two weeks later, four of the five control monkeys that were treated with the gel alone were infected with the virus. None of the macaques treated with glycerol monolaurate showed evidence of infection in these first two weeks, although Haase notes that one of the monkeys did later develop an infection.

Those treated with glycerol monolaurate also produced less Mip-3α than the control animals — suggesting that the treatment reduces the immune response that helps HIV to spread.

Battle-scarred

Despite those results, some researchers are reluctant to back the idea of taking glycerol monolaurate into human trials. The compound is a surfactant, and trials with another surfactant — the spermicide nonoxynol-9 — not only failed to protect women from HIV, but increased their risk of infection. "At the moment, the jury would be quite sceptical of a surfactant," says Ian McGowan, an immunologist at the University of Pittsburgh School of Medicine in Pennsylvania who has studied microbicides as a principal investigator in the Microbicide Trials Network. "This product would have an uphill path to get to the clinic."

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Haase has heard such criticism before, most notably in reviews of his applications for research funding. He counters that repeated use of nonoxynol-9 was found to cause inflammation and lesions in the vagina and cervix, yet his safety studies have thus far shown no evidence that glycerol monolaurate causes such damage1.

Meanwhile, Robin Shattock, an HIV researcher at St George's, University of London, says that the latest results do not rule out the possibility that glycerol monolaurate is simply destroying the virus directly, as most surfactants are thought to do. An approach that targets the immune system would be interesting, says Shattock, "but the evidence as presented is at best circumstantial".

Nevertheless, the results should stimulate more research aimed at tackling the early events after infection says Sharon Hillier, another principal investigator in the Microbicide Trials Network. "They're provocative," she says. As for glycerol monolaurate, Hillier says the compound is "going to require more attention before we know whether or not it has promise as a microbicide". 

  • References

    1. Li, Q. et al. Nature Advanced online publication doi:10.1038/nature07831 (2009).
    2. Witcher, K. J., Novick, R.P. & Schlievert, P. M. Clin. Diag. Lab. Immunol. 3, 10-13 (1996). | ChemPort |
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