Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120

Barak, Ohr; Goshen, Inbal; Ben‐Hur, Tamir; Weidenfeld, Joseph; Taylor, Anna N.; Yirmiya, Raz

doi:10.1016/s0006-8993(02)02280-1

Cited by 51 publications

(35 citation statements)

References 53 publications

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“…During HIV-1 infection, cells can release specific viral products (82,107,113), which may induce apoptosis in bystander cells. In CNS-based cells, it has been shown that HIV-1 infection can lead to the production and release of proinflammatory cytokines (9,26,83,114), which are neurotoxic. It is believed that induction of apoptosis in the CNS occurs through the direct cytopathic effects of viral proteins and/or indirectly via the release of soluble cellular factors (35).…”

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases

Acheampong

Parveen

Muthoga

et al. 2005

J Virol

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The lentiviral protein Nef plays a major role in the pathogenesis of human immunodeficiency virus type I (HIV-1) infection. Although the exact mechanisms of its actions are not fully understood, Nef has been shown to be essential for the maintenance of high-titer viral replication and disease pathogenesis in in vivo models of simian immunodeficiency virus infection of monkeys. Nef has also been suggested to play a pivotal role in the depletion of T cells by promoting apoptosis in bystander cells. In this context, we investigated the ability of extracellular and endogenously expressed HIV-1 Nef to induce apoptosis in primary human brain microvascular endothelial cells (MVECs). Human brain MVECs were exposed to baculovirus-expressed HIV-1 Nef protein, an HIV-1-based vector expressing Nef, spleen necrosis virus (SNV)-Nef virus (i.e., SNV vector expressing HIV-1 Nef as a transgene), and the HIV-1 strain ADA and its Nef deletion mutant, ADA⌬Nef. We observed that ADA Nef, the HIV-1 vector expressing Nef, and SNV-Nef were able to induce apoptosis in a dose-dependent manner. The mutant virus with a deletion in Nef was able to induce apoptosis in MVECs to modest levels, but the effects were not as pronounced as with the wild-type HIV-1 strain, ADA, the HIV-1-based vector expressing Nef, or SNV-Nef viruses. We also demonstrated that relatively high concentrations of exogenous HIV-1 Nef protein were able to induce apoptosis in MVECs. Gene microarray analyses showed increases in the expression of several specific proapoptotic genes. Western blot analyses revealed that the various caspases involved with Nef-induced apoptosis are processed into cleavage products, which occur only during programmed cell death. The results of this study demonstrate that Nef likely contributes to the neuroinvasion and neuropathogenesis of HIV-1, through its effects on select cellular processes, including various apoptotic cascades.

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Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases

Acheampong

Parveen

Muthoga

et al. 2005

J Virol

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“…RT-PCR, ELISA, and biological assays have also demonstrated IL-1β levels are elevated in HIVinfected macrophage/astroglia cocultures (Genis et al 1992;Epstein and Gendelman 1993). Moreover, the application of HIV-1 Tat protein to rat microglial cultures (Nicolini et al 2001) and the intracerebroventricular injection of HIV-1 envelope protein gp120 into rats (Barak et al 2002) have both been shown to stimulate IL-1β production. Notably, the behavioral abnormalities associated with gp120 injections were attenuated with IL-1 antagonist pretreatment.…”

Section: Interleukin-1βmentioning

confidence: 97%

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

Keblesh

Xiong

2008

J Neuroimmune Pharmacol

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Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD), a severe form of HIV-associated neurocognitive disorders (HAND), describes the cognitive impairments and behavioral disturbances which afflict many HIV-infected individuals. Although the precise mechanism leading to HAD is incompletely understood, it is commonly accepted its progression involves a critical mass of infected and activated mononuclear phagocytes (brain perivascular macrophages and microglia) releasing immune and viral products in the brain. These cellular and viral products induce neuronal dysfunction and injury via various signaling pathways. Emerging evidence indicates voltage-gated potassium (K v ) channels, key regulators of cell excitability and animal behavior (learning and memory), are involved in the pathogenesis of HAD/HAND. Here we survey the literature and find that HAD-related alterations in cellular and viral products can increase neuronal K v channel activity, leading to neuronal dysfunction and cognitive deficits. Thus, neuronal K v channels may be a new target in the effort to develop therapies for HAD and perhaps other inflammatory neurodegenerative disorders.

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“…[17][18][19][20] Moreover, antagonism (or genetic deletion) of cytokine activity has been found to ameliorate or reverse various symptoms of sickness behavior in cytokine or immune-challenged laboratory animals. 17,19,[21][22][23][24][25][26][27][28][29][30][31] Given the relationship among glucocorticoids, proinflammatory cytokines and behavior, we hypothesized that virally (MCMV)-infected mice rendered glucocorticoid deficient by ADX would exhibit exaggerated proinflammatory cytokine release accompanied by evidence of increased behavioral change as assessed by open-field behavior. Behavioral observation of mice in an open field is a standard paradigm for the study of locomotor activity and exploration.…”

Section: Introductionmentioning

confidence: 99%

“…32,33 Moreover, open-field behavior has been shown to be altered in cytokine-treated and infected animals as well as animals with autoimmune disease. 21,28,[34][35][36][37][38][39][40][41][42] In addition, since TNF-alpha has been demonstrated to mediate MCMV-induced consequences on survival, we examined the possibility that TNF-alpha might also contribute to behavioral alterations in MCMV-infected animals. To abrogate TNF-alpha activity, TNF-alpha receptor 1 (TNFRp55) knockout (TNF-R1-KO) mice were employed.…”

Section: Introductionmentioning

confidence: 99%

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

Silverman

MacDougall

et al. 2006

Mol Psychiatry

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Endogenous glucocorticoids restrain proinflammatory cytokine responses to immune challenges such as viral infection. In addition, proinflammatory cytokines induce behavioral alterations including changes in locomotor/exploratory activity. Accordingly, we examined proinflammatory cytokines and open-field behavior in virally infected mice rendered glucocorticoid deficient by adrenalectomy (ADX). Mice were infected with murine cytomegalovirus (MCMV), and open-field behavior (36 h post-infection) and plasma concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 (42 h post-infection) were assessed. Compared to sham-ADX-MCMV-infected animals, ADX-MCMV-infected mice exhibited significant reductions in total distance moved, number of center entries, and time spent in center. These behavioral alterations were accompanied by significantly higher plasma concentrations of TNF-alpha and IL-6, both of which were correlated with degree of behavioral change. To examine the role of TNF-alpha in these behavioral alterations, open-field behavior was compared in wild-type (WT) and TNF-R1-knockout (KO), ADX-MCMV-infected mice. TNF-R1-KO mice exhibited significantly attenuated decreases in number of rearings, number of center entries and time spent in center, but not distance moved, which correlated with plasma IL-6. Given the potential role of brain cytokines in these findings, mRNA expression of TNF-alpha, IL-1 and IL-6 was assessed in various brain regions. Although MCMV induced increases in proinflammatory cytokine mRNA throughout the brain (especially in ADX animals), no remarkable differences were found between WT and TNF-R1-KO mice. These results demonstrate that endogenous glucocorticoids restrain proinflammatory cytokine responses to viral infection and their impact on locomotor/exploratory activity. Moreover, TNF-alpha appears to mediate cytokine-induced changes in open-field behaviors, especially those believed to reflect anxiety.

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Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120

Cited by 51 publications

References 53 publications

Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases

Human Immunodeficiency Virus Type 1 Nef Potently Induces Apoptosis in Primary Human Brain Microvascular Endothelial Cells via the Activation of Caspases

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

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