Researchers at The Wistar Institute have discovered the mechanism that keeps herpes simplex virus 1 (HSV-1) activation restricted to a single gene for months or even years.
To escape detection by the body's immune system, the latent virus works to silence genes that would cause it to replicate. In this dormant state, only a tiny fragment of the virus genome, a single gene called the Latency-Associated Transcript gene (LAT), remains active. The researchers have identified an insulator, a stretch of DNA about 800 bp long, that serves as a physical barrier between active and inactive regions of the virus genome.
"By establishing an insulator in early latency, the herpes virus can protect this one small region of the genome from silencing, allowing infected cells to survive," says Jumin Zhou, Ph.D., an associate professor and senior author of the study.
To see if insulators play a role in silencing viral genes during the latent phase, the scientists studied cells infected with HSV-1. The studies showed that during a latent period, the virus binds to a host protein called CTCF. This protein is known to act as an insulator in mammals and in fruit flies. The findings also revealed that the viral DNA binds to CTCF in the same manner as the host DNA binds to the protein.
"By binding in this manner, we believe the CTCF protein was interacting with other viral proteins to form a type of insulator in the virus structure," Dr. Zhou says.
To verify that it was an insulator at work, the researchers then inserted copies of the structure into fruit fly embryos to see if they could block the activity driven enhancers during development. The research showed that the insulator element blocked enhancer activities in the eye tissue of fruit flies and in human cells in culture. The study also showed that HSV-1 chromatin is organized in a manner similar to the host chromatin.
The findings appear in the May issue of the Journal of Virology.