Microbicides suffered a stark clinical setback recently: In January, two Phase III trials of the microbicide Ushercell were halted because preliminary results at some trial sites indicated that the gel might increase the risk of HIV infection in women who used it. (See BioWorld Today, Feb. 1, 2007.)

But those working to prevent HIV transmission in the developing world continue to pin high hopes on microbicides. The reasons are not entirely medical. Indeed, one of the biggest advantages that microbicides have over condoms are that they can be used by women without any sort of cooperation from men - which often is not forthcoming.

In a paper published online by Nature Medicine on March 4, 2007, researchers provide surprising findings on the earliest steps of HIV infection, as well as a new factor to consider in designing microbicides.

The experiments described in the paper suggested that langerin, a surface protein on Langerhans cells, protects against HIV infection - the opposite of what was currently believed.

HIV ultimately does its damage by infecting T cells, thus destroying the very cells that are supposed to fend it off. But T cells are usually far from the entering virus, and so HIV needs to hitch a ride to get to them.

Conventional wisdom has it that it does so by infecting two types of dendritic cells that are found in genital mucosa: Langerhans cells, which express langerin, and DC cells, which express DC-SIGN.

Teunis Geijtenbeek, a postdoctoral researcher at Vrije Universiteit (Free University) Medical Center in Amsterdam, the Netherlands, and the senior author of the Nature Medicine paper, told BioWorld Today that there are studies showing that langerin helps HIV infect T cells, but those studies used high concentrations of virus. He and his colleagues used viral concentrations that are more representative of the actual HIV concentration during infection, and "if you look at different concentrations of virus, langerin is protective."

Using cultured Langerhans cells, Geijtenbeek and his team showed that langerin-expressing cells, like DC-SIGN-expressing cells, do indeed take up the virus. But "in stark contrast to DC-SIGN, langerin prevents HIV transmission," he said. What the scientists found was that Langerhans cells taking up HIV promptly chew it up. "You only become infected once you block langerin," he said.

Geijtenbeek said that as long as langerin is functional, Langerhans cells form a barrier between HIV and DC-SIGN-expressing DC cells, which are concentrated in the epithelial layer and "don't mix" with Langerhans cells. HIV infection occurs when langerin expression is disrupted, which happens if there is an injury to mucosal cells or if Langerhans cells otherwise are activated.

The research could explain why HIV infection is a relatively rare event; not nearly every sexual encounter with an infected person leads to infection. Whether it also explains what happened with Ushercell is unclear; those trial data still are being evaluated, and Geijtenbeek noted the experiments described in Nature Medicine were not set up to determine whether his team's findings have any relationship to Ushercell's recent clinical setback.

But such a relationship does appear mechanistically plausible: "From the literature, it appears that microbicides such as cellulose sulphate might induce minor inflammations of the urogenital tract," either by the gel or by the HIV-killing compound in it, Geijtenbeek said. Such inflammation will activate Langerhans cells, which will decrease the amount of langerin on the cell-surface, he said, and "our data imply that a decrease in langerin expression will prevent its protective function."