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The Journal of Neuroscience, April 4, 2007, 27(14):3703-3711; doi:10.1523/JNEUROSCI.5522-06.2007
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Neurobiology of Disease
HIV-1 Vpr Causes Neuronal Apoptosis and In Vivo Neurodegeneration
Gareth J. Jones,1 * Nicola L. Barsby,2,3 * Éric A. Cohen,4 Janet Holden,5 Kim Harris,3 Peter Dickie,2 Jack Jhamandas,3 andChristopher Power1,2,3 1Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada T2N 4N1, Departments of 2Medical Microbiology and Immunology and 3Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2, 4Institut de Recherches Cliniques de Montréal and Department of Microbiology and Immunology, University of Montreal, Montreal, Quebec, Canada H2W 1R7, and 5Department of Pathology, St. Paul's Hospital, Vancouver, British Columbia, Canada V6Z 1Y6
Correspondence should be addressed to Dr. Christopher Power, Department of Medicine, University of Alberta, 6–11 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2. Email: chris.power{at}ualberta.ca
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.
Key words: Vpr; HIV-1; dementia; transgenic mouse; apoptosis; neuron
Received Sept. 29, 2006; accepted Feb. 5, 2007.
Correspondence should be addressed to Dr. Christopher Power, Department of Medicine, University of Alberta, 6–11 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2. Email: chris.power{at}ualberta.ca
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