Experimental Topical Microbicide Offers Convenient, Long-lasting Protection Against Genital Herpes, Study Suggests

Deborah Palliser, Ph.D.The study, carried out in mice and published in Cell Host & Microbe, represents a major step toward developing a vaginal microbicide that offers women convenient, long-lasting protection against herpes infection. Such a microbicide might also help in controlling the AIDS epidemic, since the blisters caused by genital herpes make people more susceptible to HIV infection. The study's principal investigators were Deborah Palliser, Ph.D., assistant professor of microbiology & immunology at Einstein and Judy Lieberman, M.D., Ph.D., professor of pediatrics, Harvard Medical School.

An estimated one in five American adults is infected with herpes simplex virus 2 (HSV-2), which causes the sexually transmitted disease known as genital herpes. Most people don't realize they're infected, since symptoms are often mild and can be mistaken for other conditions. When symptoms do occur, they usually appear as blisters on or around the genitals or rectum. When the blisters break, they leave tender sores that usually take two to four weeks to heal. HSV-2 infection is incurable and persists in the body indefinitely, although the number of outbreaks tends to decrease over time.

The most effective way to prevent the transmission of HSV-2 is to avoid sexual contact during an active outbreak and to use condoms for sexual contact between outbreaks. When an outbreak occurs, promptly taking the suppressive antiviral drug valacyclovir can help minimize symptoms and reduce the risk of transmitting the virus.

The microbicide in this study is based on RNA interference (RNAi), a mechanism cells use to protect their genetic machinery from viruses and other threats. RNAi employs short, double-stranded RNAs called small interfering RNAs, or siRNAs. In 2001, scientists discovered that synthetic siRNAs can induce RNA interference in mammalian cells — a finding that has triggered interest in harnessing this strategy for biomedical research and drug development.

The HSV-2 microbicide used in this study inactivates two genes via RNA interference. One siRNA targets a viral gene, thereby silencing virus immediately following application, but suppression lasts for only a couple of days. The second siRNA — specific for a cell-surface protein used by HSV-2 to dock onto cells it infects — takes a few days to silence the gene, but then confers suppression for a week.

By combining the fast-acting-but-short-lived RNAi with the slower-acting-but-long-lived RNAi, the researchers created a vaginal microbicide offering protection that was both immediate (even warding off an HSV-2 "challenge" given shortly before the microbicide was applied) and sustained (protecting against HSV-2 challenge for a week after application).

"A good microbicide for a sexually transmitted disease must offer long-term protection — compliance will be problematic if it has to be applied immediately before sexual intercourse," says Dr. Palliser. "Our microbicide, with its two siRNAs, provided sustained and uninterrupted protection against HSV-2 infection. And equally important, we achieved these results without causing inflammation of vaginal tissue — a side effect observed with other siRNAs that also risks neutralizing a microbicide's benefits. We're hopeful that this experimental microbicide can be turned into a cost-effective therapy for use in developing countries where up to 80 percent of the population is infected with HSV-2." The researchers are currently working to refine the microbicide and as yet have no plans for clinical trials.

In addition to Dr. Lieberman, Dr. Palliser's coauthors are lead author Yichao Wu, and Francisco Navarro, Ashish Lal, and Emre Basar, of Harvard Medical School, Cambridge, Mass; Rajendra K. Pandey and Muthiah Manoharan of Alnylam Pharmaceuticals, Cambridge, Mass.; and Yang Feng and Sandra J. Lee of the Dana Farber Cancer Institute, Boston, Mass.