Microbicide May Eventually Prevent Transmission of HIV

Laurie Barclay, MD

March 06, 2009

March 6, 2009 — In monkeys, the antimicrobial compound glycerol monolaurate (GML) blocks transmission of simian immunodeficiency virus (SIV), which is similar to HIV, according to the results of a study published online March 4 in Nature. Although results of trials with other microbicides in preventing HIV transmission have proved disappointing, the investigators in this study are hopeful that similar compounds might in the future be used to reduce HIV transmission in humans.

"After 25 years, an effective vaccine for HIV is still on the distant horizon, so not only vaccines but all research into ways to prevent the continued spread of this lethal virus remain critically important," principal investigator Ashley Haase, MD, from the Department of Microbiology, University of Minnesota Medical School in Minneapolis, said in a news briefing. "If GML as a topical microbicide can add to our prevention, it could contribute to saving millions of lives."

This research group first showed that when rhesus macaque (Macacca mulatta) monkeys are vaginally exposed to SIV, the resulting inflammatory response to the virus actually promotes rather than hinders establishment of infection by recruiting CD4+ T cells targeted by SIV. The mechanism uses an outside-in endocervical mucosal signaling system involving MIP-3a (also known as CCL20) and plasmacytoid dendritic cells, as well as the CCR51 cell-attracting chemokines produced by these cells, in conjunction with the immune and inflammatory responses to infection innate in both the cervix and vagina.

SIV then uses the recruited CD4+ T cells to spread infection both locally and throughout the body. GML applied vaginally blocks this inflammatory response, thereby suppressing infection even after repeated viral exposure.

"So even though it sounds counterintuitive, halting the body's natural defense system might actually prevent transmission and rapid spread of the infection," Dr. Haase said. "That's where GML comes in."

GML, a compound naturally occurring in breast milk, is considered by the US Food and Drug Administration to be safe and is widely used as an antimicrobial and anti-inflammatory agent in cosmetics and in foods such as ice cream. It has demonstrated activity against several different toxins and microbes and has been shown to block MIP-3a and other cytokines and chemokines that promote the immune response.

Furthermore, previous research by coinvestigator Pat Schlievert, PhD, also from the University of Minnesota, showed efficacy of GML against toxic shock syndrome.

"GML is exceptionally inexpensive, is widely used in foods and cosmetics, and is easy to formulate in many ways for vaginal use," Dr. Schlievert said. "The compound has been demonstrated in vitro to inhibit the growth of nearly all sexually transmitted disease microorganisms and other causes of vaginal infections without affecting normal bacteria. Its use by women may significantly improve overall vaginal health."

In the experiments reported in Nature, 9 monkeys received daily vaginal application of warming gel with GML added, while 3 monkeys received warming gel alone as a placebo. No adverse effects were noted with GML.

"GML is recognized as safe and is already approved for acute human use, but we were now able to show that GML could be safely applied every day for months," Dr. Schlievert said.

One hour after vaginal application of GML or vehicle, 5 GML-treated and 5 control animals were inoculated vaginally with doses of SIV sufficient to infect 50% of cells in tissue culture. Four hours later, the monkeys were again treated with GML or vehicle and then given a second dose of SIV.

Evidence of transmission in terms of blood-borne SIV was monitored for 2 weeks. Treatments and viral challenges were repeated in monkeys with no evidence of infection, up to a total of 4 similarly large doses of SIV. Although 4 of 5 of the monkeys in the control group became infected with SIV, none of the 5 monkeys treated with GML showed any evidence of acute infection.

"As an extension of that safety study, we continued to treat animals with GML, and the surprising, great outcome of that experiment was that all 5 of the animals treated with GML were protected against systemic acute infection," Dr. Haase said.

Ultimately, it is hoped that this demonstration of GML as an effective preventative agent of SIV infection will lead to development of a safe and inexpensive microbicide to prevent HIV transmission in women.

"If we keep treating people, and we don't do anything on the prevention side, the [HIV] pandemic will just continue to grow and grow," Dr. Haase said. "We want to be circumspect about the claims that we make right now, but we have a promising lead here that could really contribute to the prevention story."

Caveats are that this method will not treat existing infection and that more research and development are needed before it could be used to help prevent HIV transmission. This includes further testing in animals, developing a dosing and a delivery method that will improve compliance, longer-term follow-up studies to monitor for appearance of occult infections, and finally, human clinical trials.

"This is actually one of the most exciting things that I've participated in, because...I think it can have a major impact on transmission of HIV in the world, but it can also have a major impact on women's vaginal health in general, preventing a variety of sexually transmitted diseases," Dr. Schlievert concluded.

The National Institutes of Health supported this study, which involved collaboration between the University of Minnesota Medical School, School of Public Health and College of Pharmacy; the Wisconsin National Primate Research Center at the University of Wisconsin-Madison; and the National Cancer Institute.

Nature. Published online March 4, 2009.

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