HIV Neurotoxicity: Potential Therapeutic Interventions

Wallace, David R

doi:10.1155/JBB/2006/65741

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HIV Neurotoxicity: Potential Therapeutic Interventions

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Author(s): David R. Wallace ^*

Publication date (Electronic): 2006

Journal: Journal of Biomedicine and Biotechnology

Publisher: Hindawi Publishing Corporation

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Abstract

Individuals suffering from human immunodeficiency virus type 1 (HIV-1) infection suffer from a wide range of neurological deficits. The most pronounced are the motor and cognitive deficits observed in many patients in the latter stages of HIV infection. Gross postmortem inspection shows cortical atrophy and widespread neuronal loss. One of the more debilitating of the HIV-related syndromes is AIDS-related dementia, or HAD. Complete understanding of HIV neurotoxicity has been elusive. Both direct and indirect toxic mechanisms have been implicated in the neurotoxicity of the HIV proteins, Tat and gp120. The glutamatergic system, nitric oxide, calcium, oxidative stress, apoptosis, and microglia have all been implicated in the pathogenesis of HIV-related neuronal degeneration. The aim of this review is to summarize the most recent work and provide an overview to the current theories of HIV-related neurotoxicity and potential avenues of therapeutic interventions to prevent the neuronal loss and motor/cognitive deficits previously described.

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Most cited references 103

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CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity.

P Bezzi, M Domercq, L Brambilla … (2001)

Astrocytes actively participate in synaptic integration by releasing transmitter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the chemokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the ensuing signaling cascade is the rapid extracellular release of tumor necrosis factor-alpha (TNFalpha). Autocrine/paracrine TNFalpha-dependent signaling leading to prostaglandin (PG) formation not only controls glutamate release and astrocyte communication, but also causes their derangement when activated microglia cooperate to dramatically enhance release of the cytokine in response to CXCR4 stimulation. We demonstrate that altered glial communication has direct neuropathological consequences and that agents interfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120IIIB. Our results identify a new pathway for glia-glia and glia-neuron communication that is relevant to both normal brain function and neurodegenerative diseases.

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The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis.

Alireza Minagar, Paul Shapshak, Robert Fujimura … (2002)

Macrophage/microglia (M phi) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood-brain barrier, behave as one of the immune effector cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M phi, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS). HAD primarily involves subcortical gray matter, and both HAD and MS affect sub-cortical white matter. AD is a cortical disease. The process of M phi and astrocytes activation leading to neurotoxicity share similarities among the three diseases. Human Immunodeficiency Virus (HIV)-1-infected M phi are involved in the pathogenesis of HAD and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). In AD, M phis produce these molecules and are activated by beta-amyloid proteins and related oligopeptides. Demyelination in MS involves M phi that become lipid laden, spurred by several possible antigens. In these three diseases, cytokine/chemokine communications between M phi and astrocytes occur and are involved in the balance of protective and destructive actions by these cells. This review describes the role of M phi and astrocytes in the pathogenesis of these three progressive neurological diseases, examining both beneficent and deleterious effects in each disease. Copyright 2002 Elsevier Science B.V.

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HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress.

M Mattson, Karl A. Nath, I I Kruman (1998)

Patients infected with HIV-1 often exhibit cognitive deficits that are related to progressive neuronal degeneration and cell death. The protein Tat, which is released from HIV-1-infected cells, was recently shown to be toxic toward cultured neurons. We now report that Tat induces apoptosis in cultured embryonic rat hippocampal neurons. Tat induced caspase activation, and the caspase inhibitor zVAD-fmk prevented Tat-induced neuronal death. Tat induced a progressive elevation of cytoplasmic-free calcium levels, which was followed by mitochondrial calcium uptake and generation of mitochondrial-reactive oxygen species (ROS). The intracellular calcium chelator BAPTA-AM and the inhibitor of mitochondrial calcium uptake ruthenium red protected neurons against Tat-induced apoptosis. zVAD-fmk suppressed Tat-induced increases of cytoplasmic calcium levels and mitochondrial ROS accumulation, indicating roles for caspases in the perturbed calcium homeostasis and oxidative stress induced by Tat. An inhibitor of nitric oxide synthase, and the peroxynitrite scavenger uric acid, protected neurons against Tat-induced apoptosis, indicating requirements for nitric oxide production and peroxynitrite formation in the cell death process. Finally, Tat caused a delayed and progressive mitochondrial membrane depolarization, and cyclosporin A prevented Tat-induced apoptosis, suggesting an important role for mitochondrial membrane permeability transition in Tat-induced apoptosis. Collectively, our data demonstrate that Tat can induce neuronal apoptosis by a mechanism involving disruption of calcium homeostasis, caspase activation, and mitochondrial calcium uptake and ROS accumulation. Agents that interupt this apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in AIDS patients. Copyright 1998 Academic Press.

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Author and article information

Journal

Journal ID (nlm-ta): J Biomed Biotechnol

Journal ID (publisher-id): JBB

Title: Journal of Biomedicine and Biotechnology

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1110-7243

ISSN (Electronic): 1110-7251

Publication date (Print): 2006

Publication date (Electronic): 2006

Volume: 2006

Electronic Location Identifier: 65741

Affiliations

Department of Pharmacology and Physiology and Department of Forensic Sciences, Center for Health Sciences, Oklahoma State University, Tulsa, OK 74107-1898, USA

Author notes

*David R. Wallace: walladr@ 123456chs.okstate.edu

Article

DOI: 10.1155/JBB/2006/65741

PMC ID: 1510947

PubMed ID: 17047310

SO-VID: 3022d9b5-b20e-4003-9691-ae1e5b4e1010

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 1 December 2005

Date revision received : 21 February 2006

Date accepted : 27 February 2006

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HIV Neurotoxicity: Potential Therapeutic Interventions

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Most cited references 103

CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity.

The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis.

HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress.

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