title: HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors.
abstract: BACKGROUND
  Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties.
  
  
  METHODS
  Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection.
  
  
  RESULTS
  Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p<0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p<0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p<0.05).
  
  
  CONCLUSIONS
  HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada; Department of Physiology and Pharmacology and Hotchkiss Brain Institute, University of Calgary, Bangkok, Thailand.
authors.forename: Shaona
authors.initials: S
authors.lastname: Acharjee
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: William G
authors.initials: WG
authors.lastname: Branton
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada; Department of Pharmacology, Mahidol University, Bangkok, Thailand.
authors.forename: Pornpun
authors.initials: P
authors.lastname: Vivithanaporn
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Maingat
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Paul
authors.affiliation: Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dickie
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, Canada.
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada; Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Canada; Department of Psychiatry, University of Alberta, Edmonton, Canada. Electronic address: chris.power@ualberta.ca.
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000276:immunology / Q000821:virology; D001921:Brain / Q000276:immunology / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000821:virology*; D009043:Motor Activity; D012701:Serotonin / Q000378:metabolism; D065853:Spatial Learning / Q000502:physiology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050483:Dopamine Plasma Membrane Transport Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D012701:Serotonin; D004298:Dopamine
keywords: CCL2; Dopamine transporter; HIV-1; Hyperactivity; Mania; Microglia; Nef; Striatum