siRNA-Laced Intravaginal Gel Wipes Out HSV-2 in Experimental Models

A TOPICAL TREATMENT THAT KILLS herpes simplex virus type 2 (HSV-2) and that has long staying power may be available in the future. The experimental microbicidal solution, consisting of cholesterol-conjugated small interfering RNA (chol-siRNA), was tested in female mice that were given a lethal dose of the virus. The solution, delivered intravaginally, had a remarkably protective effect. No inflammatory, autoimmune, or other adverse effects, including interference with normal cell function, were seen, according to Judy Lieberman, MD, PhD, senior investigator, of the Immune Disease Institute at Harvard Medical School.

The mechanism of action, termed “RNA interference,” disables an HSV-2 gene (UL29) and protein (nectin-1), preventing virus replication and take-up of the virus by the host cell. Developed by a team led by Lieberman and Deborah Palliser, PhD, at Albert Einstein College of Medicine, RNA interference is an advance over a technology that Lieberman and colleagues developed in 2005.

The technology uses 2 types of siRNA that fortify each other’s effects, delivering a double-punch against HSV-2. The siRNA strands are attached to cholesterol to facilitate cell penetration. The chol-siRNA strand that targets UL29 silences the virus immediately on contact, but suppression is temporary, lasting only a few days. The effect is backed by another chol-siRNA strand that targets the HSV-2 receptor protein nectin-1, preventing the virus from docking onto a host cell. This process requires a few days to take effect but provides viral suppression for a week.

Among the potential benefits of this technology is that an intravaginal or rectal microbicidal solution or gel for human use could be discreetly applied several days before-or after-sexual activity to deliver a protective effect. This is particularly valuable for women who, because of interpersonal circumstances or cultural norms, may not be able to refuse or otherwise prepare themselves for activity that may put them at risk for sexually transmitted disease (STD).

Among other benefits, this technology could have a profound effect on perinatal mother-to-child transmission of HSV-2 infection. It would also help prevent HIV transmission, which is facilitated in the setting of active HSV-2 infection.

Use of antimicrobial gels for the prevention of STDs-particularly HIV infection-has been under study. Although certain formulations have proved beneficial in thwarting male-to-male and female-to-male transmission of disease, finding a formulation that effectively protects women has been elusive. Human studies will be required to see whether Lieberman and Palliser’s work is the longed-for breakthrough. They are about to initiate studies on how similar technology can be used to combat HIV infection.

The study, which was supported by the NIH, was the joint effort of researchers from Harvard and Albert Einstein College of Medicine. To read more about the study, see the following citation: Wu Y, Navarro F, Lal A, et al. Durable protection from herpes simplex virus-2 transmission following intravaginal application of siRNAs targeting both a viral and host gene. Cell Host Microbe. 2009;5:84-94.