The Promise of an Effective Vaginal Microbicide
Jeffrey Laurence, M.D. and Rowena Johnston, Ph.D.
February 19, 2009—While scientists continue to debate the finer points of microbicide design, there are certain elements that most agree would characterize an ideal product. In addition to preventing or at least reducing the risk of acquiring HIV, it might also prevent other sexually transmitted infections (STIs). It should not require application right before intercourse, as this can be inconvenient and lead to a significant drop in its appropriate application; and it should not harm the natural tissue barriers to infection, as this can increase the risk of infection. It is this last requirement that many prototype HIV vaginal microbicides have failed to meet. Several products have in fact led to an increase in HIV transmission during testing.
amfAR fellow Dr. Deborah Palliser, writing in the January issue of Cell Host & Microbe, offers a promising new way to address many of these impediments to microbicide design. Over the years, Dr. Palliser and associates, working at Albert Einstein College of Medicine and Harvard University, have tested their microbicide concepts in mice using the genital herpes virus HSV-2. They have focused on a highly specific anti-virus strategy: small pieces of genetic material known as siRNAs. These siRNAs can be tailor-made to jam the production of specific proteins, including proteins that are constituent parts of, or are necessary to, disease-causing pathogens. By changing the genetic sequence of these siRNAs, virtually any pathogen can be suppressed. Combining several siRNAs, each one specific to its own target, into a single cream or gel might permit inhibition of a panoply of genital infections, from herpes and HIV to chlamydia, papillomavirus, and several other prevalent STIs.Two years ago we reported on related amfAR-supported work by Dr. Palliser and her colleagues. At that time, although the potency of siRNAs in general was (and is) not in question, when used alone their protection was short-lived, and frequent application would be required. When they were mixed with lipids capable of prolonging their activity, damage to sensitive vaginal tissue actually facilitated viral infection. In her most recent study, Dr. Palliser was able to overcome this problem by linking cholesterol to the siRNAs, then stabilizing this material through a chemical modification involving phosphorothioate (PS). PS protected the siRNAs from being broken down by vaginal and seminal fluids.
A single local application of two of these cholesterol/PS-siRNAs, one directed against the herpes virus itself and another blocking the HSV-2 receptor nectin-1, protected mice against vaginal challenge with HSV-2 for up to a week. The dual targeting was key to their success. While the siRNA against the virus was effective for only a day, the addition of the cellular target required for HSV-2 to enter a cell, the nectin-1 receptor, extended the anti-HSV-2 activity to a week. No toxicity of these siRNAs was noted.
Any means to reduce the rate of new HIV infections would be profoundly welcome. The question now is whether this new siRNA approach to blocking HSV-2 can be modified to form the basis of a microbicide that prevents HIV transmission. We will keep you updated on this continually evolving story.
Dr. Jeffrey Laurence is amfAR’s senior scientific consultant. Dr. Rowena Johnston is amfAR’s vice president of research.