Herpes Remains Latent by Producing Self-inhibitory MicroRNA

Molecular virologists have identified the mechanism used by the herpes simplex virus 1 (HSV1) to remain alive but latent in nerve cells until stimulated to renewed activity by excessive sunlight, fever, or other stresses.

During its latent phase, the virus does not replicate and practically the only molecular product that is being made is a type of RNA called latency-associated transcript RNA or LAT RNA. While in the latent state the virus is not susceptible to antiviral treatment.
Writing in the July 2, 2008, online edition of the journal Nature, senior author Dr. Bryan Cullen, professor of molecular genetics and microbiology from Duke University (Durham, NC, USA), said, "It has always been a mystery what this product, LAT RNA, does. Usually viral RNAs exist to make proteins that are of use to the virus, but this LAT RNA is extremely unstable and does not make any proteins.”

Results presented in this study revealed that LAT functioned as a primary microRNA (miRNA) precursor that encoded four distinct miRNAs in HSV-1 infected cells. The investigators showed that one of the miRNAs, miR-H2-3p, was able to reduce expression of ICP0 protein--a viral immediate-early transcriptional activator that is important for productive HSV-1 replication--but did not significantly affect ICP0 messenger RNA levels. When faced with stress, the amount of ICP0 mRNA exceeded the amount of inhibitory miRNA, and the virus was stimulated to begin replication.

"Inactive virus is completely untouchable by any treatment we have. Unless you activate the virus, you cannot kill it,” said Dr. Cullen. "Once the virus is active, a patient would then take acyclovir, a drug that effectively kills replicating HSV1. In principle, you could activate and then kill all the virus in a patient. This would completely cure a person, and you would never get another cold sore.”


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