Harvard researchers silence herpes in mice using a topical treatment

Working in mice, a team of researchers led by scientists at Harvard have developed a topical treatment that stops herpes infections before and after exposure to the sexually transmitted virus.

The new treatment, described today in the journal Cell Host & Microbe, not only keeps the virus from replicating, but it also blocks the herpes virus from entering cells.

The discovery, which works by silencing two genes involved in herpes infections, builds on earlier experiments in mice reported three years ago in Nature that harnessed RNA interference to keep the herpes simplex type 2 virus from making copies of itself once it had penetrated cells.

The topical microbicide worked when it was given to mice a week before they were infected and also a few hours after they were exposed to lethal amounts of the virus. Among mice that didn't receive the treatment, 20 percent survived, but 80 percent of mice that were given the treatment survived.

"The most important aspect is that we were able to provide sustained protection from transmission," co-author Dr. Judy Lieberman of Harvard Medical School said in an interview. "It presents the possibility of developing something that could be clinically useful."

RNA interference is a natural phenomenon that can switch genes on or off. Since its discovery a decade ago, scientists have made it a mainstay of laboratory experiments to reveal how cells work. Realizing its promise as a way to prevent or treat disease has been more daunting. Two challenges have been how to deliver the small RNAs where they were needed and how to keep them working long enough to be effective.

Lieberman has been studying RNA interference as a way to suppress HIV since 2001, when the gene-silencing mechanism was confirmed in mammals. Herpes is a leading risk factor for HIV because the inflammation it causes in tissues makes women more vulnerable to HIV infection.

A topical solution, or microbicide, brings the small interfering RNAs to the cells lining the vagina that the herpes viruses try to enter. That attacks the delivery problem, and the one-two punch of blocking the virus from entering the cell and then preventing it from spreading if it did get inside tackles the durability problem.

Long-lasting protection might have another benefit, Lieberman said.

"When thinking about developing a topical agent to protect women against HIV, one of the main obstacles for any microbicide would be compliance," she said. "Most types of agents have to be administered just before you had sex and that's an incredible hurdle."

Dr. John L. Sullivan, vice provost for research at University of Massachusetts Medical School and a longtime HIV researcher, called the work's implications "huge." He was not involved in the study

"I think this is very exciting data, I think it's a great proof of concept, and I think it's in an area where we need new advances," he said. "The idea that one could have a microbicide that works is huge. This really shows that RNAi opens the door for those possibilities."

Lieberman's study was funded by grants from the National Institutes of Health and Centers for AIDS Research.

Her co-authors on the Cell Host & Microbe paper include two scientists from Alnylam Pharmaceuticals, part of a continuing basic-science collaboration between the Cambridge company and her lab to work on treatments for HIV. The microbicide used against herpes in mice wouldn't directly affect HIV because it infects immune cells, not the epithelial cells that line openings in the body where the herpes virus enters.

Last month Lieberman received one of the first six Massachusetts Life Sciences Center grants to support industry-academic partnerships. She will work with Epic Therapeutics of Norwood, a subsidiary of Baxter Healthcare, to develop a gel that could be used to apply the topical microbicide against herpes.

The RNAi-based microbicide would need to be researched further in mice and other animals before being tested in humans, she said.

"A microbicide that treats or protects women from transmission of herpes could have a public health effect," she said. "This could potentially be used as a way of protecting women from ... all the discomfort and pain but also from transmitting the virus to a sexual partner."