A new study has revived hopes for an effective vaginal microbicide in preventing the transmission of HIV. A compound widely used in cosmetics and foods can block transmission of the virus by interfering with the immunological steps to infection, researchers report in Nature this week.

 

Representation of virus expansion after SIV exposure. Green crosses: clusters of infected cells. Image: A. Haase

The compound's microbicide potential has so far been tested in vivo only in monkeys, but in vitro results suggest it also works against the human version of the virus.

"I think this is a really exciting study," said Melissa Robbiani, senior scientist at the Population Council, a New York research and policy nonprofit focused on AIDS and reproductive health. To date, most microbicides under development work by simply blocking the virus from entering the body or target cells, said Robbiani, who was not involved in the research, "whereas this is actually targeting the immune system and modulating immune function."

With a vaccine for HIV still years away, researchers have long pinned their hopes on a topical product that could be applied to the vagina to stem the virus's spread. The past few years, though, have brought dismaying results in microbicide development. In February, 2008, a promising microbicide gel called Carraguard was deemed ineffective in a Phase 3 study. And the February before that, negative results from a Phase III trial sank a potential microbicide called Ushercell.

Ashley Haase at the University of Minnesota, the current study's main author, and his colleagues began by mapping the innate immune response initiated locally in the vagina upon exposure to the virus. They observed growing clusters of infected immune cells in the vaginas of monkeys exposed to simian immunodeficiency virus (SIV), the monkey version of HIV. First, plasmacytoid dendritic cells rushed to the scene; those spurred a chemokine and cytokine response, which in turn brought CD4+ T cells. The T cells would then be infected by the virus, fueling its spread throughout the body, Haase and coauthor Patrick Schlievert explained in a press conference yesterday (March 3).

The team reasoned that "if you could break one of the links in that chain, you would break the influx of target cells that the virus needed" to infect further cells, Haase said. They tested the compound glycerol monolaurate (GML) in that role because other research shows it appears to block the growth of microorganisms such as Staphylococcus and Chlamydia, and because it was already FDA-approved for oral and topical use. (GML, an ester, is commonly used as an emulsifier in cosmetics and foods such as ice cream.) In cultured human vaginal epithelial cells exposed to HIV, they found, GML blocked the production of molecules that appear during inflammation and that are thought to increase susceptibility to HIV infection.

The researchers then made up a 5% GML solution dissolved in a lubricant called KY warming gel, and applied it to five rhesus macaques that had been vaginally exposed to SIV. The GML gel blocked acute infection in all five of the monkeys tested, while four out of five control moneys, exposed to the virus in the same way, became infected. "The results, we think, are very encouraging," said Haase in the press conference.

The study not only demonstrated the efficacy of GML in blocking the virulence of immunodeficiency viruses, Robbinani noted, but it also "provided additional evidence for the innate response role in infection" and teased out the roles of different immune cells in propagating the virus. "That's important just from a biology standpoint," she said.

Haase and Schlievert noted that further animal testing is needed before GML can be tested in humans. One of the five monkeys in which the gel was tested initially appeared to be protected from SIV, but months later developed the infection, they said; long-term studies will have to be done to understand how often such "occult infections" occur. "And we also need to find much better dosing schedules [that are] more applicable to the real world," Haase said in the press conference.

Also, they cautioned, the compound's effectiveness in monkeys can't be extrapolated to humans. "Vaginal transmission by rhesus macaques is regarded by many as the best animal model for HIV transmission, but it's still an animal model," Haas said.

Haase et al's study isn't the only positive recent news on the microbicide front. Last month, researchers from an international collaboration called the Microbicide Trials Network reported promising results from a trial of another microbicide in development, PRO2002, a polymer intended to interfere in interactions between HIV and its target cells. Those findings, from a Phase II safety and efficacy study, prompted the Gates Foundation to pump $100 million into the International Partnership for Microbicides, a Maryland-based organization working on HIV microbicide development.