Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment

Seth W. Perry; Harris A. Gelbard

doi:10.1128/9781555815691.ch11

Chapter 11 : Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment

Authors: Seth W. Perry¹, Harris A. Gelbard²

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Affiliations: 1: Center for Aging and Developmental Biology, Kornberg Medical Research Institute, Departments of Neurology, Pediatrics, Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; 2: Center for Aging and Developmental Biology, Kornberg Medical Research Institute, Departments of Neurology, Pediatrics, Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642

Content Type: Monograph

Publication Year: 2009

Category: Viruses and Viral Pathogenesis

Book DOI: 10.1128/9781555815691

Chapter DOI: 10.1128/9781555815691.ch11

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Abstract:

In 1991, a revision of the terminology was made by the American Academy of Neurology AIDS Task Force, which developed the term human immunodeficiency virus (HIV)-1-associated cognitive motor complex (HIV-CMC), to encompass both the milder HIV-1- associated minor cognitive motor disorder (HIV-MCMD) and the more severe HIV-1-associated dementia complex (HIV-DC) (American Academy of Neurology AIDS Task Force, 1991). Although the advent of highly active antiretroviral therapies (HAART) has made great strides in extending life for AIDS patients, this longer life span may present increasing opportunity for HIV dementia (or HAD) to develop. HIV-1 encephalitis, the histo- and neuropathological correlate of central nervous system (CNS) HIV infection and HAD, occurs in most but not all cases of HAD. Infiltration of infected and/or activated immune cells from the periphery is increased with HIV infection and likely to be essential for development of HAD. Passage of infected cells or virus across the blood-brain barrier (BBB) results in the presence of activated immune cells in the brain, primarily macrophages and microglia but also astrocytes, which are thought to be directly causal to developing HAD. Continuous exposure to these noxious molecules is not necessary for progressive neuronal dysfunction and death. As a consequence of these generalized pathogenic mechanisms, numerous molecules and signaling pathways are secreted and activated that are thought to be involved in precipitating the pathophysiology of HAD, many of which share functions in both normal cellular signaling and other neurodegenerative diseases.

Citation: Perry S, Gelbard H. 2009. Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment, p 137-149. In Goodkin K, Shapshak P, Verma A (ed), The Spectrum of Neuro-AIDS Disorders. ASM Press, Washington, DC. doi: 10.1128/9781555815691.ch11

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Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment

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FIGURE 1

Schematic diagram of some purported HIV neurotoxin-induced neuronal dysfunctions in HIV dementia. Candidate HIV neurotoxins such as Tat, TNF-α, PAF, gp120, and others are thought to activate excitotoxic pathways involving glutamate receptor activation, calcium influx, increased excitotoxic synaptic activity, alterations in mitochondrial membrane potential (Δψm), productions of ROS, and ultimately synapse loss and neuronal cell death if left unchecked. Alterations in the activity of GSK-3β or other signal transduction pathways (not diagrammed here) may lead to changes in synaptic activity and/or direct neuronal apoptosis. The goal of adjunctive therapeutics for HAD is to interrupt the cycle of cellular dysfunction before deficits become chronic and before significant synapse loss and/or neuronal cell death occurs.

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FIGURE 1

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FIGURE 2

Tat upregulates synaptic proteins in rat cortical neurons. Treatment of rat cortical neurons for 24 h with 2.5 µg of Tat/ml up-regulated several key proteins involved in synaptic structure and function, including phosphorylated synapsin, total synapsin, and calcium calmodulin kinase II. Semiquantitative changes in protein expression were determined by densitometric analysis of mean band intensities from Western blots and were expressed as change with Tat treatment relative to control. A representative example of control and Tat synapsin bands (cut from blot film image after digital background subtraction) is shown. Percent values were generated from the average band intensity of duplicate samples (from separate treatment wells) per condition, run on the same gel. Treatment conditions were performed in duplicate or triplicate for at least two separate blots per target protein, and all changes were significant (P < 0.05, analysis of variance and Student’s t test).

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FIGURE 2

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