Anna Cliffe, PhD
Anna Cliffe, PhD, an associate professor in the Department of Microbiology, Immunology, and Cancer Biology, was awarded a $2.7 million R01 grant from the National Institutes of Health for a project titled “The role of ATRX in both promoting the establishment of HSV latency and restricting reactivation.”
The Cliffe lab studies mechanisms of Herpes Simplex Virus (HSV) latent infection and reactivation in neurons. More than 60% of the U.S. population is infected with the virus, which can cause a range of disease outcomes, including oral and genital lesions, keratitis, and encephalitis, and potentially contribute to the development of Alzheimer’s disease. The virus persists for life as a latent infection of neurons and can periodically reactivate in response to a variety of stimuli to cause disease.
The new R01 grant will aim to determine the mechanistic role of a host protein ATRX (Alpha thalassemia/mental retardation syndrome X-linked) in promoting entry into latent infection in neurons and preventing reactivation. ATRX is an abundant neuronal protein that protects neurons from aberrant gene expression during stress. Abigail Whitford, a graduate student in the Cliffe lab, has found that ATRX also protects neurons from HSV reactivation. A subpopulation of latent viral genomes in neurons associate with ATRX, and these genomes are less likely to reactivate. The project aims to understand how ATRX silences HSV gene expression in neurons and determine whether targeting ATRX is a potential therapeutic strategy to limit HSV reactivation in response to a variety of stimuli. An alternative to be tested is that latent viral genomes associate with distinct proteins as an evolutionary “bet-hedging” approach, enabling different genomes to reactivate in response to different stimuli. Mutations in ATRX are associated with neurodevelopmental disease in addition to glioma. Therefore, this project will inform on the mechanisms of HSV latency and shed light on ATRX function in neurons, potentially informing the study of other diseases.
Seed funds for this project were provided by the Owens Family Foundation. Abigail Whitford was previously supported by the UVA Infectious Disease T32 Training grant with principal investigators Alison Criss, PhD, and William Petri, MD, PhD, and a UVA Wagner Fellowship. David Kashatus, PhD, is a collaborator on this project.
Filed Under: Research