title: Delineating HIV-associated neurocognitive disorders using transgenic models: the neuropathogenic actions of Vpr.
abstract: HIV-associated neurocognitive disorders (HAND) represent a constellation of neurological disabilities defined by neuropsychological impairments, neurobehavioral abnormalities and motor deficits. To gain insights into the mechanisms underlying the development of these disabilities, several transgenic models have been developed over the past two decades, which have provided important information regarding the cellular and molecular factors contributing to the neuropathogenesis of HAND. Herein, we concentrate on the neuropathogenic effects of HIV-1 Vpr expressed under the control of c-fms, resulting transgene expression in myeloid cells in both the central and peripheral nervous systems. Vpr's actions, possibly through its impact on cell cycle machinery, in brain culminate in neuronal and astrocyte injury and death through apoptosis involving activation of caspases-3, -6 and -9 depending on the individual target cell type. Indeed, these outcomes are also induced by soluble Vpr implying Vpr's effects stem from direct interaction with target cells. Remarkably, in vivo transgenic Vpr expression induces a neurodegenerative phenotype defined by neurobehavioral deficits and neuronal loss in the absence of frank inflammation. Implantation of another viral protein, hepatitis C virus (HCV) core, into Vpr transgenic animals' brains stimulated neuroinflammation and amplified the neurodegenerative disease phenotype, thereby recapitulating HCV's putative neuropathogenic actions. The availability of different transgenic models to study HIV neuropathogenesis represents exciting and innovative approaches to understanding disease mechanisms and perhaps developing new therapeutic strategies in the future.
authors.affiliation: Department of Medicine (Neurology), University of Alberta, Heritage Medical Research Center, Edmonton, AB, Canada. chris.power@ualberta.ca
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hui
authors.forename: Pornpun
authors.initials: P
authors.lastname: Vivithanaporn
authors.forename: Shaona
authors.initials: S
authors.lastname: Acharjee
authors.forename: Maria
authors.initials: M
authors.lastname: Polyak
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1