title: Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence.
abstract: BACKGROUND
  Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1's biology and pathogenicity. Despite the increasing availability of antiretroviral therapy, HIV-associated dementia (HAD) continues to be a devastating consequence of HIV-1 infection of the brain although the underlying disease mechanisms remain uncertain. Herein, molecular diversity within the HIV-1 non-structural gene, Vpr, was examined in RNA sequences derived from brain and blood of HIV/AIDS patients with or without HIV-associated dementia (HAD) together with the ensuing pathobiological effects.
  
  
  RESULTS
  Cloned brain- and blood-derived full length vpr alleles revealed that amino acid residue 77 within the brain-derived alleles distinguished HAD (77Q) from non-demented (ND) HIV/AIDS patients (77R) (p < 0.05) although vpr transcripts were more frequently detected in HAD brains (p < 0.05). Full length HIV-1 clones encoding the 77R-ND residue induced higher IFN-α, MX1 and BST-2 transcript levels in human glia relative to the 77Q-HAD encoding virus (p < 0.05) but both viruses exhibited similar levels of gene expression and replication. Myeloid cells transfected with 77Q-(pVpr77Q-HAD), 77R (pVpr77R-ND) or Vpr null (pVpr(-))-containing vectors showed that the pVpr77R-ND vector induced higher levels of immune gene expression (p < 0.05) and increased neurotoxicity (p < 0.05). Vpr peptides (amino acids 70-96) containing the 77Q-HAD or 77R-ND motifs induced similar levels of cytosolic calcium activation when exposed to human neurons. Human glia exposed to the 77R-ND peptide activated higher transcript levels of IFN-α, MX1, PRKRA and BST-2 relative to 77Q-HAD peptide (p < 0.05). The Vpr 77R-ND peptide was also more neurotoxic in a concentration-dependent manner when exposed to human neurons (p < 0.05). Stereotaxic implantation of full length Vpr, 77Q-HAD or 77R-ND peptides into the basal ganglia of mice revealed that full length Vpr and the 77R-ND peptide caused greater neurobehavioral deficits and neuronal injury compared with 77Q-HAD peptide-implanted animals (p < 0.05).
  
  
  CONCLUSIONS
  These observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.
authors.affiliation: Department of Medicine University of Alberta, Edmonton, AB, T6G 2S2, Canada. chris.power@ualberta.ca.
authors.forename: Hong
authors.initials: H
authors.lastname: Na
authors.forename: Shaona
authors.initials: S
authors.lastname: Acharjee
authors.forename: Gareth
authors.initials: G
authors.lastname: Jones
authors.forename: Pornpun
authors.initials: P
authors.lastname: Vivithanaporn
authors.forename: Farshid
authors.initials: F
authors.lastname: Noorbakhsh
authors.forename: Nicola
authors.initials: N
authors.lastname: McFarlane
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Maingat
authors.forename: Klaus
authors.initials: K
authors.lastname: Ballanyi
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Pardo
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001769:Blood / Q000821:virology; D001921:Brain / Q000821:virology*; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D064547:Myxovirus Resistance Proteins; D009457:Neuroglia / Q000276:immunology / Q000821:virology; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D056189:Viral Tropism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D019204:GTP-Binding Proteins; D016898:Interferon-alpha; D064547:Myxovirus Resistance Proteins; D012367:RNA, Viral; D054325:vpr Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C579070:Mx1 protein, mouse