title: Persistent infection by HSV-1 is associated with changes in functional architecture of iPSC-derived neurons and brain activation patterns underlying working memory performance.
abstract: BACKGROUND
  Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.
  
  
  METHODS
  Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.
  
  
  RESULTS
  HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10(-4); 2-back, P = 1.39 × 10(-5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.
  
  
  CONCLUSIONS
  The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA; These authors contributed equally to the article.
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Aiuto
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA; These authors contributed equally to the article.
authors.forename: Konasale M
authors.initials: KM
authors.lastname: Prasad
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA;
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Upton
authors.affiliation: Department of Biology, University of Bari "Aldo Moro", Bari, Italy;
authors.forename: Luigi
authors.initials: L
authors.lastname: Viggiano
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors.forename: Jadranka
authors.initials: J
authors.lastname: Milosevic
authors.affiliation: Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Raimondi
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA;
authors.forename: Lora
authors.initials: L
authors.lastname: McClain
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA;
authors.forename: Kodavali
authors.initials: K
authors.lastname: Chowdari
authors.affiliation: Department of Genetics and The Human Genome Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ;
authors.forename: Jay
authors.initials: J
authors.lastname: Tischfield
authors.affiliation: Department of Genetics and The Human Genome Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ;
authors.forename: Michael
authors.initials: M
authors.lastname: Sheldon
authors.affiliation: Department of Genetics and The Human Genome Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ;
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Moore
authors.affiliation: Stanley Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD;
authors.forename: Robert H
authors.initials: RH
authors.lastname: Yolken
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Molecular Genetics & Biochemistry, University of Pittsburgh, Pittsburgh, PA;
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kinchington
authors.affiliation: Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA vishwajitnl@upmc.edu.
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000503:physiopathology*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology* / Q000821:virology; D005260:Female; D059907:Functional Neuroimaging; D015870:Gene Expression; D020869:Gene Expression Profiling; D006561:Herpes Simplex / Q000473:pathology / Q000503:physiopathology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics*; D012559:Schizophrenia / Q000150:complications / Q000503:physiopathology* / Q000821:virology; D012565:Schizophrenic Psychology; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D012367:RNA, Viral
keywords: fMRI; herpes; herpes simplex virus type 1; induced pluripotent stem cells; memory