16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

HIV-1 VPR EXERTS NEUROPATHOGENIC EFFECTS CAUSING NEURONAL APOPTOSIS AND GLIAL CELL TYPE-DEPENDENT NEUROINFLAMMATION

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0202

Barsby N.¹, Jones G.², Jhamandas J.³, Dickie P.³, Cohen E.⁴, Power C.^5
1 University of Alberta, Medical Microbiology and Immunology, Edmonton, Canada, ² University of Calgary, Calgary, Canada, ³ University of Alberta, Edmonton, Canada, ⁴ University of Montreal, Montreal, Canada, ⁵ University of Alberta, Medicine, Edmonton, Canada

BACKGROUND: Although the mechanisms for HIV neuropathogenesis remain uncertain, the HIV-1 accessory protein, viral protein R (Vpr), has been suspected to participate in the progression to HIV-associated dementia (HAD). Vpr has been shown to induce apoptosis in neurons and mediates immune dysregulation. Our objective here was to define the mechanisms by which Vpr induced apoptosis in neurons and regulated neuroinflammation.

METHODS: Using soluble Vpr and a transgenic mouse expressing Vpr under the c-fms promoter, in monocytoid cells, we investigated effects of Vpr on neurons and glial cells.

RESULTS: Vpr was more frequently detected in HIV+/HAD+ brains than HIV non-demented brains, in monocytoid cells. In parallel with activation of a caspase-9 and caspase-3, Vpr neurotoxicity was associated with suppression of the anti-apoptotic molecule, Akt. Vpr also exerted excitatory effects on rat basal forebrain neurons in vitro and in terms of behavioural changes among Vpr-implanted and Vpr transgenic mice. Analysis of inflammatory molecule expression in astrocytes and monocytoid cells following Vpr treatment showed reduced or enhanced expression of pro-inflammatory cytokines depending on the glial cell type. Supernatants from Vpr-treated astrocytic and monocytoid cells caused neuronal death. Moreover, supernatants from bone marrow-derived macrophages, isolated from Vpr transgenic mice, induced Vpr-dependent neurotoxicity. However, no specific induction of inflammatory gene transcript levels was observed in the Vpr transgenic brains compared to littermate controls.

CONCLUSIONS: Vpr-induced neuronal apoptosis occurs by both direct and indirect mechanisms. Direct application of soluble Vpr causes apoptosis involving Akt suppression and caspase-9 activation while the indirect effects may be mediated by excitation of glial cells.

Download PDF of this abstract.

Download Power Point Presentation.

2006-08-13
ThAa0202

Copyright © 2006 - International AIDS Society (IAS). All information and content relating to the abstracts from the 16th International AIDS Conference, such as text, graphics, logos, button icons, images, audio clips, and software is protected by copyright. Permission is hereby granted for the non-commercial use or reproduction of the information on this web site, provided that the use of such information is accompanied by an acknowledgement that IAS is the source of the information and the name of the author of the article.

AEGiS is a 501c(3) not-for-profit organization made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, GlaxoSmithKline, the National Library of Medicine, Roche / Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 2006. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2006. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. Permission is hereby granted for the non-commercial use or reproduction of the information herein, provided that the use of such information is accompanied by an acknowledgement that IAS is the source of the information and the name of the author of the article.