Identification of ATRX as a Restriction Factor during Herpes Simplex Virus Latent Infection and Characterization of Phase I of Reactivation
Year: 2025
Type: dissertation
Abstract: Herpes simplex virus-1 (HSV-1) establishes a lifelong latent infection in neurons and reactivation from this latent state is the cause of recurrent oral and ocular infections, herpes simplex keratitis, and encephalitis. Neuronal conditions during initial HSV-1 infection have a long-term impact on latency, modulating how responsive latent genomes are to reactivation and, therefore, their ability to cause disease. We find that type I interferon (IFNα) exposure during initial infection results in a more restrictive form of HSV-1 latency and the deposition of a repressive heterochromatin mark, H3K9me3, and its reader, ATRX (alpha-thalassemia/ mental retardation, X-linked). ATRX is highly abundant in neurons and is essential for maintaining cellular heterochromatin during neuronal stress. We find that ATRX restricts de novo lytic gene expression, promotes latency establishment, and inhibits reactivation. This work highlights how neuronal-specific factors limit HSV-1 infection to promote latency and restrict reactivation. In addition to understanding what factors limit neuronal HSV-1 infection, we also investigated the neuronal pathways HSV-1 commandeers to reactivate. Using novel systems to study HSV-1 latency, we find that reactivation in both an ex vivo murine system and an in vitro human system can be triggered with physiologically relevant triggers. In an ex vivo system we confirm that reactivation is biphasic and dependent on the neuronal stress kinases dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK). This work aids in the development of potential therapeutic interventions by identifying neuron-specific factors involved in HSV-1 latency and reactivation.
Source: Libra
DOI: 10.18130/a1j6-xn09
Author: Abigail Whitford
Institution: University of Virginia
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6906721208
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