Research scientists at Harvard have discovered a novel way to protect mice against herpes simplex virus 2 (HSV-2). Herpes simplex virus 2, also known as genital herpes, is a co-factor for the transmission of AIDS. Protection against HSV-2 could help protect against the transmission of AIDS.
Herpes Simplex Virus Type 2
Approximately 20 percent of the U.S. population is infected with herpes simplex virus 2, also known as genital herpes. In Africa, that number is about 80 percent. HSV-2 infections triple the risk of becoming infected with HIV, the virus that causes AIDS.
HSV-2 is not fatal in humans. However, it does cause chronic infection and genital ulcers, resulting in inflammation and erosion of the layers of skin on the surfaces inside and outside the genital areas. These layers normally act as a barrier to the AIDS virus. However, when this barrier is weakened by the HSV-2 viral infection, it is much easier to transmit the AIDS virus.
Protection against HSV-2 infections, therefore, could help decrease the transmission of the AIDS virus.
siRNA and RNAi
The term siRNA stands for small interfering RNA. RNA stands for ribonucleic acid, which is very similar, though not identical, in structure to DNA. RNA plays many roles inside a cell. One of the main roles is to transcribe the information contained within DNA.
RNA molecules that transcribe the information from DNA are known as mRNA, or messenger RNA. mRNA is a single-stranded RNA molecule. It carries information from the DNA in the nucleus of a cell into the cytoplasm, where it is then translated into protein.
siRNA molecules interfere with this process. They are short, double-stranded RNA molecules specifically designed to interfere with the expression of a particular gene or gene fragment. They have gained a lot of attention recently, due to their ability to suppress the activity of a variety of disease-causing genes. The process by which siRNA interferes with gene expression is known as RNAi, or RNA interference.
siRNA Protects Against HSV-2
Harvard research scientists have shown that siRNA molecules can protect against herpes simplex virus 2 infections in mice. They found that mice given siRNAs designed to interfere with the genital herpes virus proteins were protected against a lethal dose of the virus, while mice given siRNAs not directed against HSV-2 viral proteins were not protected.
Increasing Protection Against HSV-2
In the original experiments, the Harvard researchers found that the protection the siRNA provided against HSV-2 infection in mice was short lived. They administered the siRNA molecules using lipid transfection, a process that uses lipids, or fats, to cause a cell to absorb nucleic acid. While the researches used the lipid transfection process to help the cells absorb the siRNA nucleic acid, they discovered that this process unfortunately also helped transmit the virus nucleic acid. Increasing the amount of siRNA delivered to the cell offered no more protection for the mice, as it also increased viral infection.
Researchers did, however, discover a way to deliver siRNA that did not increase viral infection. They attached the siRNAs to a cholesterol molecule. The cholesterol molecules made it possible for the siRNA to pass through the cell membrane and be taken up by the host cell. A topical solution made of these molecules was fully absorbed into the vaginal tissue of mice.
This method was almost as effective at delivering the siRNAs to the cells as the lipid transfection process and protected the mice longer. When challenged with the HSV-2 virus for up to one week after being given the siRNA, the treated mice were still protected.
Targets of the siRNA Molecules
Originally, siRNA molecules were directed against two different HSV-2 viral genes, a gene that codes for a glycoprotein and a gene that codes for a DNA binding protein called UL29. The siRNA directed against the UL29 DNA binding protein worked the best. Later studies used siRNAs directed against UL29 in combination with an HSV receptor protein called nectin-1.
Treatment for Humans
The success of the mice model system for HSV-2 protection by siRNA molecules raises hopes that the same type of treatment can be used in humans, but this treatment in humans is not yet available. RNAi is promising because of the ease of compliance. It could be administered up to one week in advance of a virus challenge and still offer protection.
According to the lead scientist at Harvard, Dr. Judy Lieberman, the siRNA "could either be administered to a person already infected to reduce viral shedding, pain, and transmission to a sexual partner, or it could be administered to those who are not infected to protect them." However, before using the microbicide on humans, tests will first need to be done on monkeys.
RNAi-based drugs are generating a lot of excitement, not only for their promise in protecting against HSV-2 infections, but also for the hopes that they can protect against other diseases as well. Targets for siRNA by various research groups include AIDS, flu, hepatitis, malaria and ALS, also known as Lou Gehrig's disease.
Despite the promise, a lot more work needs to be done before this method becomes a reality in the treatment of human diseases.