title: Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes.
abstract: Herpesviruses are highly prevalent and maintain lifelong latent reservoirs, thus posing challenges to the control of herpetic disease despite the availability of antiviral pharmaceuticals that target viral DNA replication. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 (lysine-specific demethylase 1) and a member of the JMJD2 family (Jumonji C domain-containing protein 2). Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and blocks infection and reactivation in vitro. We demonstrate that viral infection can be epigenetically suppressed in three animal models of herpes simplex virus infection and disease. Treating animals with the monoamine oxidase inhibitor tranylcypromine to inhibit LSD1 suppressed viral lytic infection, subclinical shedding, and reactivation from latency in vivo. This phenotypic suppression was correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Therefore, epi-pharmaceuticals may represent a promising approach to treat herpetic diseases.
authors.affiliation: Department of Ophthalmology and Department of Microbiology, Immunology, and Parasitology, LSU Eye Center, Louisiana State University Health Science Center School of Medicine, New Orleans, LA 70112, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Hill
authors.affiliation: Department of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Debra C
authors.initials: DC
authors.lastname: Quenelle
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Cardin
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Vogel
authors.affiliation: Department of Ophthalmology and Department of Microbiology, Immunology, and Parasitology, LSU Eye Center, Louisiana State University Health Science Center School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Clement
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Bravo
authors.affiliation: Department of Ophthalmology and Department of Microbiology, Immunology, and Parasitology, LSU Eye Center, Louisiana State University Health Science Center School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Foster
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20852, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Bosch-Marce
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Raja
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115, USA. Harvard Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20852, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Krause
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115, USA. Harvard Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. tkristie@niaid.nih.gov.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kristie
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D016679:Genome, Viral; D006168:Guinea Pigs; D006566:Herpesviridae Infections / Q000378:metabolism*; D056466:Histone Demethylases; D051379:Mice; D008807:Mice, Inbred BALB C; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000502:physiology*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012008:Recurrence; D014191:Tranylcypromine / Q000737:chemistry; D014621:Vagina / Q000821:virology; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects; D017201:Virus Shedding
chemical_list: D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating