Once herpes simplex infects a person, the virus takes up permanent residence inside nerve cells, periodically reigniting infection and causing cold sores or genital lesions to recur.
How the virus maintains this sleep-wake mode has been unknown. Now, HMS scientists in the Department of Microbiology and Immunobiology and the Department of Biological Chemistry and Molecular Pharmacology have used a mouse model to identify the molecular regulator of this viral lifestyle: a host cell protein called CTCF, or cellular CCCTC-binding factor.
The researchers found that CTCF enables herpes simplex to establish latent infections in the body’s sensory neurons. Preventing CTCF from binding to the viral DNA weakens the virus’s ability to rekindle infection and its associated symptoms.
Previous research at HMS showed that the virus’s sleep-wake cycle is regulated by the interaction of two sets of genes. Latency-associated transcript genes, or LAT genes, turn off the transcription of viral RNA, which induces viral latency, while a gene called ICP0 produces a protein that activates genes that stimulate viral replication, leading to active infection. Past studies have shown that the LAT gene and the ICP0 gene can act in opposition, inducing the virus to alternate between dormant and active states, but can also act in concert to promote latency or reactivation. The genes also occupy overlapping sites on the viral genome.
In a series of experiments, the recent study identified the sites on the virus’s DNA where the CTCF protein binds and showed that deleting the CTCF binding sites weakened the virus’s ability to awaken from its dormant state, strong evidence that the CTCF protein is a key regulator of the sleep-wake cycle in herpes simplex infections.
Lee JS, et al., mBio, January/February 2018