Cliffe Lab

Investigating the molecular mechanisms of Herpes Simplex Virus latency and reactivation, and neuronal specific immune responses.​

Herpes simplex virus (HSV) is a human pathogen that persists for life as a latent infection of neurons. In the Cliffe lab we are trying to uncover the mechanisms of persistence by studying the fate of the viral DNA genome in neurons. We also investigate how HSV reactivates from latent infection to cause disease. Finally, because the virus persists in a highly specialized and essential long-lived cell type (a neuron), we use HSV as a tool to investigate neuronal specific responses to immune stimuli.

HSV Phase I and phase II of reactivation

Mechanisms of HSV reactivation

Our lab has developed novel in vitro models of HSV latency. Using these models, we have discovered a neuronal pathway involving activation of c-Jun N-terminal kinase (JNK), common to many stress responses, that is essential for initial HSV gene expression during reactivation. We have also found that this pathway can be activated in neurons by immune-mediated hyperexcitabilty. JNK-dependent reactivation results in a specific change to the HSV epigenome known as a histone methyl/phospho switch, which can permit gene expression to occur from repressive heterochromatin. Our studies therefore answer long-standing question as to how viral gene expression can initiate to trigger HSV reactivation.

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PML-NBs in interferon treated neurons.

Latent HSV genomes have memory

Our lab has shown that the HSV-1 latency and reactivation can be impacted by the state of the neuron during initial infection. In one study, we showed that exposure to type I IFN during initial HSV infection resulted in a repressive form of latency that is unable to reactivate. We found this was due to the formation and association of viral genomes with PML nuclear bodies. In a recent study, we have found that cell stress during initial infection has the opposite effect and results in latency that is more capable of reactivating. Both these studies highlight how neurons and the viral genome possess memory of previous stimuli. We are working on how these intersect with epigenetic changes to the host and/or virus.

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Latent HSV-1 genomes co-localize with H3K27me3

Epigenetics of HSV infection

The outcome of HSV infection is linked to the type of chromatin associated with viral genomes. Our lab is investigating the mechanisms by which host and viral factors impact chromatin association following entry of naked viral genomes into the nucleus of different cell types. We are also interested in the mechanisms of remodeling during reactivation, especially during initial exit from latency, and how the type of silent heterochromatin on latent genomes impacts the ability of the virus to reactivate.

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News All News »

Jan 2024

Our paper on the role of the host cell stress transcription factor, c-Jun, in HSV-1 reactivation has been published in Journal of Virology (read more here).  While there are multiple…

Dec 2023

Congratulations to Sara Dochnal on very successfully defending her PhD. Throughout her graduate studies, Sara has developed a novel model of HSV-1 latency and reactivation using a recombinant "Stayput-GFP" virus.…

July 2023

Anna gave a talk at the International DEEP-DV Summer School 2023 in Hamburg and got to hear about some really amazing science being performed as part of the DEEP-DV consortium…

July 2023

Sara Dochnal gave a spotlight talk at her first in-person International Herpesvirus Workshop in Missoula, Montana. Plus she was awarded a Merit Award. The lab is super proud of all…

May 2023

The first PhD graduation for the Cliffe lab. Congratulations to Dr. Sean Cuddy!!!!