An analysis of HIV-1-associated inflammatory products in brain tissue of humans and SCID mice with HIV-1 encephalitis

Persidsky, Yuri; Buttini, Manuel; Limoges, Jenae; Bock, Paul J.; Gendelman, Howard Eliot

doi:10.3109/13550289709031186

Cited by 118 publications

(80 citation statements)

References 43 publications

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“…The mechanisms underlying neuronal injury for HAD are mirrored in our laboratory and in HIVE SCID mouse models of human disease. These two model systems demonstrate the importance of HIV-infected or activated MPs in inducing neuronal dysfunction through the secretion of cellular and viral toxins including proinflammatory cytokines, glutamate, and a variety of excitotoxins (Genis et al, 1992;Nottet et al, 1995;Persidsky et al, 1996Persidsky et al, , 1997Anderson et al, 2003). Previous studies performed in our laboratories also demonstrated that sodium valproate induces neuroprotective effects by downregulation of Tau phosphorylation and GSK-3␤ in HIVE mice (Dou et al, 2003).…”

Section: Discussionmentioning

confidence: 70%

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Dou¹,

Ellison²,

Bradléy³

et al. 2005

J. Neurosci.

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Lithium (Li) has garnered considerable interest as a neuroprotective drug for a broad range of nervous system disorders. Its neuroprotective activities occur as a consequence of glycogen synthase kinase-3␤ (GSK-3␤) inhibition leading to downstream blockade of ␤-catenin and Tau phosphorylation. In the present study, we investigated Li-mediated neuroprotective mechanisms in laboratory and murine human immunodeficiency virus-1 (HIV-1) encephalitis (HIVE) models. In laboratory tests, Li protected neurons from neurotoxic secretions of HIV-1-infected monocyte-derived macrophages (MDMs). This neuroprotection was mediated, in part, through the phosphatidyl inositol 3-kinase/Akt and GSK-3␤ pathways. To examine the effects of Li treatment in vivo, MDMs were injected into the basal ganglia of severe combined immunodeficient mice and then Li was administered (60 mg/kg/d). Seven days after MDM injection, mice were killed and CNS tissue was collected and subjected to immunocytochemical and Western blot assays for leukocyte and neural antigens, GSK-3␤, and key kinase substrates such as ␤-catenin and Tau. Numbers of HIV-1 p24 antigen-positive MDMs were unaltered by Li treatment of HIVE mice. Similarly, the greatly increased extent of astrocyte and microglia activation in HIVE mice (10-fold and 16-fold, respectively, compared with unmanipulated controls) was also unaltered by Li. In contrast, Li restored HIVE-associated loss of microtubule-associated protein-2-positive neurites and synaptic density while reducing levels or activity of phospho-Tau Ser 202 , phospho-␤-catenin, and GSK-3␤. Electrophysiological recordings showed diminished long-term potentiation in hippocampal slices of HIVE mice that were restored by Li. Based on these data, the use of Li as an adjuvant for HIV-1-associated dementia is now being pursued.

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Section: Discussionmentioning

confidence: 70%

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Dou¹,

Ellison²,

Bradléy³

et al. 2005

J. Neurosci.

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“…81,125 In addition to chemokines and EAAs, HIV-infected or gp120-activated microglia also release inflammatory cytokines, including TNF-a and IL-1b. 46,132 Among other actions, both of these cytokines stimulate release of L-cysteine from macrophages, and pharmacologic blockade of IL-1b or antibody neutralization of TNF-a prevents this release. 60 Under physiological or pathophysiological conditions, Lcysteine can stimulate NMDARs and lead to neuronal apoptosis.…”

Section: Mechanisms Of Neuronal Injury and Death In Hadmentioning

confidence: 99%

HIV-1 infection and AIDS: consequences for the central nervous system

et al. 2005

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Infection with the human immunodeficiency virus-1 (HIV-1) can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. After infiltrating peripheral immune competent cells, in particular macrophages, HIV-1 provokes a neuropathological response involving all cell types in the brain. HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can trigger numerous downstream signaling pathways and disrupt neuronal and glial function. This review will discuss recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and potential approaches for development of future therapeutic intervention.

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“…Despite extensive evidence of pathological changes in the CNS of infected individuals, the mechanism(s) of viral entry into the brain is still not completely understood. Studies suggested that this mechanism is dependent, in part, on the transmigration of infected leukocytes across the blood-brain barrier (BBB) into the CNS (Price and Brew, 1988;Persidsky et al, 1997;Weiss et al, 1999). The BBB is composed mainly of specialized endothelial cells (ECs) in contact with astrocytes and is characterized by the presence of tight junction proteins (TJPs) between EC-EC and EC-astrocytes and selective permeability to physiological ions (Goldstein, 1988;Risau et al, 1990;Rubin and Staddon, 1999).…”

Section: Introductionmentioning

confidence: 99%

CCL2/Monocyte Chemoattractant Protein-1 Mediates Enhanced Transmigration of Human Immunodeficiency Virus (HIV)-Infected Leukocytes across the Blood–Brain Barrier: A Potential Mechanism of HIV–CNS Invasion and NeuroAIDS

Eugenín¹,

Osiecki²,

Lopez³

et al. 2006

J. Neurosci.

357

336

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An analysis of HIV-1-associated inflammatory products in brain tissue of humans and SCID mice with HIV-1 encephalitis

Cited by 118 publications

References 43 publications

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

HIV-1 infection and AIDS: consequences for the central nervous system

CCL2/Monocyte Chemoattractant Protein-1 Mediates Enhanced Transmigration of Human Immunodeficiency Virus (HIV)-Infected Leukocytes across the Blood–Brain Barrier: A Potential Mechanism of HIV–CNS Invasion and NeuroAIDS

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