Investigating the Role of Human Cytomegalovirus Protein LUNA in Regulating Viral Gene Expression during Latency
Creators: name: Lau, Jonathan
Publisher: name: Apollo - University of Cambridge Repository
Year: 2019
Subjects: subject: Cytomegalovirus
subject: Herpesvirus
subject: Virology
subject: Molecular Virology
subject: Human Cytomegalovirus
subject: Herpesvirology
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: Latency
subject: Reactivation
subject: Epigenetics
subject: Bioinformatics
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences
subject: LUNA
subject: Latency-associated
subject: Transcriptional Regulation
subject: Primary Cell
subject: HCMV
subject: CMV
subject: Viruses
subject: Infection
subject: Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: Chronic infection
subject: Medicine
subject: Medical Sciences
subject: Recombineering
subject: SUMO
subject: SUMOylation
subject: DeSUMOylation
subject: Protein
subject: PML body
subject: ND10
subject: Myeloid
subject: CD34
subject: CD14
subject: DNA Virus

description: Human cytomegalovirus (HCMV) is a widespread human herpesvirus pathogen and prototypical member of the β-herpesvirus subfamily. Like all herpesviruses, the virus establishes a lifelong latent infection following host exposure, which has the potential to reactivate periodically and contribute to recurrent disease processes. In individuals with weak or compromised immune systems, such reactivation can lead to profound pathology. Understanding how latent infections are maintained is important for uncovering how HCMV causes disease. The study of viral genes that are expressed during latent infection grants insight into how latency is regulated and how it could be therapeutically targeted. To that end, this project has sought to evaluate the functional significance of one such viral gene termed LUNA in the context of latency. In models of experimental latent infection based on primary myeloid cells, levels of viral gene transcription were found to be significantly reduced following infection with LUNA deletion mutant viruses, consistent with corresponding observable changes in post-translational histone modifications over the viral promoters of latency-associated genes. Additionally, using luciferase reporter systems, latency-associated viral gene promoters became activated in response to the expression of wild-type LUNA. Together, these findings argue for a role of LUNA in regulating viral gene expression during latent HCMV infection. One possible mechanism by which LUNA may fulfil its role is by targeting cellular ND10 structures, known intrinsic inhibitors of herpesvirus gene expression, for disruption. In support of this, latently infected cells were found to be devoid of ND10, a phenotype that was recapitulated by the direct expression of wild-type LUNA. Furthermore, mutation studies confirmed the identification of a novel deSUMOylase activity encoded by LUNA that was responsible for mediating ND10 disruption. Use of a catalytically inactive LUNA mutant in transcriptional analyses of latent infection also generated similar results as with the LUNA deletion viruses. Overall, these data support the hypothesis that LUNA serves as an important regulator of viral gene expression during latency, which is likely linked to its ability to target ND10 structures for disruption, thus raising the possibility that inhibition of deSUMOylation may serve as a novel therapeutic strategy to target latent HCMV infection.
description: • UKRI | Medical Research Council (MRC) Doctoral Training Grant • The Teresa Rosenbaum Golden Charitable Trust (UK Charity No. 9347608) • The Warden and Fellows of Robinson College in the University of Cambridge