title: HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration.
abstract: Despite the introduction of highly active antiretroviral therapy, dementia caused by human immunodeficiency virus-1 (HIV-1) infection remains a devastating and common neurological disorder. Although the mechanisms governing neurodegeneration during HIV-1 infection remain uncertain, the HIV-1 accessory protein, viral protein R (Vpr), has been proposed as a neurotoxic protein. Herein, we report that Vpr protein and transcript were present in the brains of HIV-infected persons. Moreover, soluble Vpr caused neuronal apoptosis, involving cytochrome c extravasation, p53 induction, and activation of caspase-9 while exerting a depressive effect on whole-cell currents in neurons (p < 0.05), which was inhibited by iberiotoxin. Vpr-activated glial cells secreted neurotoxins in a concentration-dependent manner (p < 0.001). Transgenic (Tg) mice expressing Vpr in brain monocytoid cells displayed the transgene principally in the basal ganglia (p < 0.05) and cerebral cortex (p < 0.01) compared with hindbrain expression. Vpr was released from cultured transgenic macrophages, which was cytotoxic to neurons and was blocked by anti-Vpr antibody (p < 0.05). Neuronal injury was observed in Tg animals compared with wild-type littermates, chiefly affecting GAD65 (p < 0.01) and vesicular acetylcholine transferase (p < 0.001) immunopositive neuronal populations in the basal ganglia. There was also a loss of subcortical synaptophysin (p < 0.001) immunoreactivity as well as an increase in activated caspase-3, which was accompanied by a hyperexcitable neurobehavioral phenotype (p < 0.05). Thus, HIV-1 Vpr caused neuronal death through convergent pathogenic mechanisms with ensuing in vivo neurodegeneration, yielding new insights into the mechanisms by which HIV-1 injures the nervous system.
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Jones
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Barsby
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
authors.forename: Janet
authors.initials: J
authors.lastname: Holden
authors.forename: Kim
authors.initials: K
authors.lastname: Harris
authors.forename: Peter
authors.initials: P
authors.lastname: Dickie
authors.forename: Jack
authors.initials: J
authors.lastname: Jhamandas
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D016336:Gene Products, vpr / Q000096:biosynthesis / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus