Spring 2007
NIAID Discovery News
Shutting Down the Genital Herpes Virus
Once acquired, herpes simplex virus (HSV) 2—a common, sexually transmitted infection that can cause painful, recurring sores around the genitals—never goes away. Although genital herpes symptoms can be controlled with antiviral drugs, preventing HSV-2 infection altogether is an important public health goal because HSV-2 infection increases a person’s risk of acquiring HIV, the virus that causes AIDS.
NIAID grantee Judy Lieberman, M.D., Ph.D., and her colleagues at Harvard Medical School in Boston made headway toward this goal by creating a fatty liquid that effectively silenced the expression of HSV-2 genes and protected mice from an otherwise lethal dose of the virus. Significantly, the liquid’s power seemed long-lasting. In one experiment, the scientists found that their product continued to have the desired effect in mouse vaginas for at least nine days.
The liquid the Boston group is developing is one of a class of experimental substances called microbicides. Several dozen microbicides are being tested in labs, animal studies, and human clinical trials. Whether formulated as a gel, cream, or foam, microbicides would be applied to the vagina prior to intercourse, giving women a discreet way to protect themselves from sexually transmitted infections. An ideal microbicide would not only be safe, easy to use, and inexpensive, it would be effective even if applied many hours or days before intercourse.
Microbicides can work in different ways. Some create an impenetrable barrier and act like a chemical condom, while others maintain the acidity of the vaginal fluid, boosting its ability to destroy germs. The substance being tested in Dr. Lieberman’s lab incorporates short strips of genetic material, called small interfering RNA (siRNA), which specifically target and “silence” the genes HSV-2 needs to reproduce and spread. Dr. Lieberman and colleagues including Deborah Palliser, Ph.D., and David Knipe, Ph.D., were the first to show an siRNA-based microbicide worked in an animal model of HSV-2 infection.
RNA Interference
Since its discovery—first in plants and insects and later in higher animals—the naturally occurring viral defense process called RNA interference (RNAi) has generated great excitement throughout the scientific world. Researchers hope to harness the gene-silencing effects of RNAi with lab-created siRNAs that can target the genetic machinery of viruses while sparing host tissue. Significant challenges remain: For example, investigators must devise a way to incorporate virus-specific siRNAs into an inert carrier and then deliver it to the appropriate body cells so that the siRNAs can do their silencing work.
Dr. Lieberman and her co-workers have shown that there are ways to work around and potentially overcome these hurdles. They mixed siRNAs targeting two HSV-2 genes with fat molecules called lipids. The siRNA-containing lipid complex was effectively taken up by both surface and deeper layers of mouse vaginal cells, and almost completely extinguished the HSV-2 genes’ activity. Importantly, the siRNA liquid did not appear to cause inflammation, suggesting that it might be a good candidate for further study as a microbicide. For clinical use, however, it would need to be formulated in a gel that could be retained in a woman’s vagina.
Aside from work on microbicide candidates, Dr. Lieberman’s lab is also trying to find ways to induce immune cells to take up siRNAs targeted against HIV genes. Unlike vaginal mucosal cells, lymphocytes do not readily take up siRNA-containing lipids. Recently, Dr. Lieberman and her colleagues reported success in overcoming this problem. They combined an siRNA with a protein fragment that enabled siRNAs to be delivered to all types of human white blood cells, including lymphocytes, macrophages, and dendritic cells, all prime targets of HIV. Dr. Lieberman and her co-workers next intend to test these siRNAs in immunodeficient mice transplanted with human blood cells that are susceptible to HIV infection.
—Anne A. Oplinger
References
Palliser, D. et al. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature DOI: 10.1038/nature04263 (2006).
Peer, D. et al. Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0608491104 (2007).
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