title: Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease.
abstract: BACKGROUND
  Epidemiological studies consistently demonstrate synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1). Higher HIV-1 loads are observed in coinfected individuals, and conversely, HIV-1 is associated with more-severe herpetic disease. A small animal model of coinfection would facilitate identification of the biological mechanisms underlying this synergy and provide the opportunity to evaluate interventions.
  
  
  METHODS
  Mice transgenic for HIV-1 provirus and human cyclin T1 under the control of a CD4 promoter (JR-CSF/hu-cycT1) were intravaginally infected with HSV-2 and evaluated for disease progression, HIV shedding, and mucosal immune responses.
  
  
  RESULTS
  HSV-2 infection resulted in higher vaginal HIV loads and genital tissue expression of HIV RNA, compared with HSV-uninfected JR-CSF/hu-cycT1 mice. There was an increase in genital tract inflammatory cells, cytokines, chemokines, and interferons in response to HSV-2, although the kinetics of the response were delayed in HIV-transgenic, compared with control mice. Moreover, the JR-CSF/hu-cycT1 mice exhibited earlier and more-severe neurological disease. The latter was associated with downregulation of secretory leukocyte protease inhibitor expression in neuronal tissue, a molecule with antiinflammatory, antiviral, and neuroprotective properties.
  
  
  CONCLUSIONS
  JR-CSF/hu-cycT1 mice provide a valuable model to study HIV/HSV-2 coinfection and identify potential mechanisms by which HSV-2 facilitates HIV-1 transmission and HIV modulates HSV-2-mediated disease.
authors.affiliation: Department of Pediatrics.
authors.forename: Briana
authors.initials: B
authors.lastname: Nixon
authors.forename: Esra
authors.initials: E
authors.lastname: Fakioglu
authors.forename: Martha
authors.initials: M
authors.lastname: Stefanidou
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Monica
authors.initials: M
authors.lastname: Dutta
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000818:Animals; D060085:Coinfection / Q000821:virology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006558:Herpes Genitalis / Q000276:immunology / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D006651:Histocytochemistry; D007249:Inflammation; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000276:immunology / Q000821:virology*; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D014621:Vagina / Q000737:chemistry / Q000821:virology; D014779:Virus Replication; D017201:Virus Shedding
chemical_list: D016207:Cytokines; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse
keywords: coinfection; female genital tract; herpes simplex virus-2; human immunodeficiency virus-1; mouse model; sexually transmitted infections