Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures

Abstract

Neuronal loss in HIV encephalopathy remains a mystery since HIV-1 productively infects macrophage and microglia and only rarely infects neurons in the central nervous system. Apoptosis is a mechanism which may account for the loss of neurons in HIV-1 infected brain. Putative toxic factors that result in neuronal cell death in HIV-1 infection include the regulatory protein Tat, since this protein is known to be released from HIV-1 infected cells. Here we show that Tat induces cell death by apoptosis in cultured human fetal neuronsproducing characteristic morphological and biochemical features associated with apoptosis. These findings suggest that Tat may play an important role as a secreted, soluble neurotoxin in HIV-1 associated dementia.

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

“…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). Furthermore, several studies suggest that HIV-1 Tat and gp120 interact with neuronally-expressed receptors to activate multiple pro-apoptotic signaling cascades in neurons Moore et al, 1997;New et al, 1997;Shi et al, 1998;Piller et al, 1999;Bonavia et al, 2001;Corasaniti et al, 2001;Haughey et al, 2001). …”

“…Apoptotic changes are seen with HIVE in both neurons and nonneuronal cells (Ramirez et al, 2001;Bonavia et al, 2001;Corasaniti et al, 2001;AdleBiassette et al, 1995;Gelbard et al, 1995;Petito and Roberts, 1995;Shi et al, 1996;Kaul et al, 2001;Shi et al, 1998;Park et al, 2001). HIV-1 is neurotoxic by inducing inflammation and through the direct release of toxic viral proteins such as Nef, Vpr, gp120 and Tat (Haughey et al, 2001;Brenneman et al, 1988;Dreyer et al, 1990;Adamson et al, 1996;New et al, 1997;Kruman et al, 1998;Yeung et al, 1998;Huang and Bond, 2000;Trillo-Pazos et al, 2000;Nath, 2002). The neurotoxicity of gp120 has been demonstrated both in primary human neuronal cultures (Lannuzel et al, 1997;Yeung et al, 1995) and in transgenic mice (Toggas et al, 1994).…”

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

“…Previous studies indicate that HIV Tat is capable of mediating neuronal apoptosis through activation of proximal monocytoid cells and secretion of neurotoxins (59,60). Exposure of human fetal neurons to neurotoxic supernatants from HIV tat-transfected monocytoid cells (Tat S/N) led to a marked reduction in MAP-2 reactivity (Fig.…”

Neuronal Apoptosis Is Mediated by CXCL10 Overexpression in Simian Human Immunodeficiency Virus Encephalitis

“…10 One broad explanation frequently advocated explaining the loss of neurons in this disease is that cellular and/or viral proteins released from the infected cells have a direct toxic effect on the neurons. [11][12][13][14][15][16][17][18] Because all parenchymal brain cells are known to express chemokine receptors, 19 and because expression of chemokines becomes dysregulated and frequently overexpressed during central nervous system (CNS) inflammation, it is possible that overexpressed chemokines in the HIV-infected brain may orchestrate the degenerative neuronal changes. 20 In earlier studies aimed at exploring factors contributing to encephalitis caused by simian human immunodeficiency virus (SHIV) in the rhesus macaque model of HIV encephalopathy, we performed chemokine microarray analysis on the brains of infected macaques with and without SHIV-E.…”