Intraventricular Injection of Human Immunodeficiency Virus Type 1 (HIV-1) Tat Protein Causes Inflammation, Gliosis, Apoptosis, and Ventricular Enlargement

Abstract

To determine the role of the Tat protein of the human immunodeficiency virus type 1 (HIV-1) in the pathogenesis of HIV-1 associated dementia, recombinant Tat was injected intraventricularly as a single or repeated dose into male Sprague-Dawley rats. Histopathological evaluation showed an initial infiltration of neutrophils one day after Tat injection, followed by macrophages and lymphocytes by 7 days. Tat-injected brains also exhibited astrocytosis, apoptotic cells, and ventricular enlargement 7 days following the last injection. Nuclear magnetic resonance spectroscopic analysis of tissue extracts of hippocampi from Tat-injected rats showed a decrease in the glutamate/g aminobutyric acid ratio. We conclude that the transient extracellular exposure of the central nervous system to Tat protein of HIV can cause a cascade of events leading to the influx of inflammatory cells, glial cell activation, and neurotoxicity.

Transient Exposure to HIV-1 Tat Protein Results in Cytokine Production in Macrophages and Astrocytes

“…These findings are consistent with our previous observations that, following a single intraventricular injection of Tat in rats, progressive glial activation and macrophage infiltration could be seen for several days, even though Tat itself could not be detected in the brain after a few hours (12). Furthermore, an exposure of Tat in the order of only milliseconds is sufficient to induce prolonged depolarization in neurons (25,40).…”

“…Tat also causes glial cell activation for several days post intracerebroventricular inoculation (12). Furthermore, a Tat-derived peptide when injected into the brain causes cytokine dysregulation (14) similar to that observed in patients with HIV infection (10,15).…”

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

“…Although the mechanisms underlying HIV-induced cell death in the nervous system are not fully understood, results presented herein suggest that underlying neurotoxic pathways are highly complex and likely to differ for each viral protein. HIV-1 viral products can be released by infected microglia and astroglia (Ensoli et al, 1990;Munis et al, 1992;Robert-Guroff et al, 1990;Chang et al, 1997;Shutt and Soil, 1999;Jones et al, 1998;Jones et al, 2000), and can also induce the production and release of proinflammatory cytokines and cellular toxins in neural cells (Yeung et al, 1995;Adamson et al, 1996;Bagetta et al, 1996a;Kaul and Lipton, 1999;Nath et al, 1999). Numerous lines of evidence suggest that extracellular proinflammatory cytokines and cellular toxins can induce neuronal apoptosis (Gabuzda et al, 1986;Gendelman et al, 1994;Shi et al, 1998;New et al, 1998;Bagetta et al, 1999;Holden et al, 1999;Zheng et al, 1999;Park et al, 2001;Takahashi et al, 1996).…”

Synergistic increases in intracellular Ca2+, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat

“…Although the astrocytes themselves can be latently infected with HIV-1 (Bagasra et al, 1996;Nath and Geiger, 1998;Brack-Werner, 1999), viral proteins such as Tat and gp120, which are released from infected macrophages/ microglia in the CNS, can also interact with uninfected astrocytes thereby disrupting their function. Tat is a transactivating, nonstructural viral regulatory protein, which is present in the extracellular fluid within the CNS of infected individuals (Hudson et al, 2000) and is intrinsically neurotoxic (Sabatier et al, 1991;Jones et al, 1998;Nath, 1999;Nath, 2002). Extracellular Tat is a potent inducer of diverse genes in a variety of cell types, and has the capacity to activate the pro-inflammatory cytokines IL-6, TNF-α and chemokines interleukin-8 (IL-8) and MCP-1.…”