The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-α

Yeung, Michael C.; Pulliam, Lynn; Lau, Allan S Y

doi:10.1097/00002030-199509020-00004

Cited by 156 publications

(45 citation statements)

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“…Human clinical and autopsy studies suggest that viral-induced inflammation and dysregulation of cytokine expression play a major role in the pathogenesis of HIV-1 infection and disease progression (Breen et al, 1990; Kedzierska and Crowe, 2001; Matsumoto et al, 1993). HIV-1 gp120-induced dysregulation of cytokine expression was also demonstrated in laboratory and animal models studies, and gp120 upregulated IL-6 and IL-8 expression in mononuclear phagocytes and glial cells (Capobianchi et al, 1997; Oyaizu et al, 1991; Yeung et al, 1995). Intrathecal and intracerebroventricular injection of gp120 in mice and rats increases IL-6 expression in the hippocampus, meninges, and spinal cord; and the IL-6 released mediated inflammatory pain in these animals (Schoeniger-Skinner et al, 2007).…”

Section: Discussionmentioning

confidence: 90%

HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood–brain barrier: modulatory effects of STAT1 signaling

Yang

Akhter

Chaudhuri

et al. 2009

Microvascular Research

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How neuroinflammatory activities affect signaling pathways leading to blood-brain barrier (BBB) injury during HIV/AIDS are currently unknown. Our previous work demonstrated that HIV-1 exposure activates pro-inflammatory genes in human brain microvascular endothelial cells (HBMEC) and showed that these genes are linked to the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Here, we report that HIV-1 gp120 protein activated STAT1 and induced interleukin (IL)-6 and IL-8 secretion in HBMEC. IL-6, IL-8, and gp120 increased monocyte adhesion and migration across in vitro BBB models. The STAT1 inhibitor, fludarabine, prevented gp120-induced IL-6 and IL-8 secretion. Inhibitors of STAT1, mitogen activated protein kinase kinase (MEK) (PD98059), and phosphatidyl inositol 3 kinase (PI3K) (LY294002), blocked gp120-induced STAT1 activation and significantly diminished IL-8-, IL-6-, and gp120-induced monocyte adhesion and migration across in vitro BBB models. These data support the notion that STAT1 plays an important role in gp120-induced inflammation and BBB dysfunction associated with viral infection. Results also suggest crosstalk between STAT1, MEK, and PI3K pathways in gp120-induced BBB dysfunction. Inhibition of STAT1 activation could provide a unique therapeutic strategy to decrease neuroinflammation and BBB dysfunction in HIV/AIDS.

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Section: Discussionmentioning

confidence: 90%

HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood–brain barrier: modulatory effects of STAT1 signaling

Yang

Akhter

Chaudhuri

et al. 2009

Microvascular Research

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“…Studies in vitro indicate that many of these products significantly modulate astrocyte physiology which in turn can alter essential interactions of astrocytes with other cells in the brain, particularly neurons. For example, exposure of cultured astrocytes to HIV-1, recombinant gp120, or viral transactivator Tat induces some of the same secretable mediators of neuropathogenesis as those produced by macrophages, including inflammatory cytokines TNF-α and IL-1β, chemokines MCP-1 and IP-10, IL-6, or neurotoxin nitric oxide [42-50]. The apparent dysregulation of astrocyte immune functions could contribute to the overall inflammatory environment in the brain.…”

Section: Introductionmentioning

confidence: 99%

Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection

Bentsman

Potash

et al. 2007

BMC Neurosci

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BackgroundHIV-1 infects human astrocytes in vitro and in vivo but the frequency of infected cells is low and its biological significance is unknown. In studies in vitro, recombinant gp120 alone can induce profound effects on astrocyte biology, suggesting that HIV-1 interaction with astrocytes and its functional consequences extend beyond the limited levels of infection in these cells. Here we determined the relative efficiencies of HIV-1 binding and infection in human fetal astrocytes (HFA), mainly at the single cell level, using HIV-1 tagged with green fluorescence protein (GFP)-Vpr fusion proteins, termed HIV-GFP, to detect virus binding and HIV-1 expressing Rev and NefGFP fusion proteins to detect productive infection.ResultsEssentially all HFA in a population bound HIV-GFP specifically and independently of CCR5 and CXCR4. The dynamics of this binding at 37°C resembled binding of an HIV fusion mutant to CD4-positive cells, indicating that most of HIV-GFP arrested infection of HFA at the stage of virus-cell fusion. Despite extensive binding, only about 1% of HFA were detectably infected by HIV-RevGFP or HIV-NefGFP, but this proportion increased to the majority of HFA when the viruses were pseudotyped with vesicular stomatitis virus envelope glycoprotein G, confirming that HFA impose a restriction upon HIV-1 entry. Exposure of HFA to HIV-1 through its native proteins rapidly induced synthesis of interleukin-6 and interleukin-8 with increased mRNA detected within 3 h and increased protein detected within 18 h of exposure.ConclusionOur results indicate that HIV-1 binding to human astrocytes, although extensive, is not generally followed by virus entry and replication. Astrocytes respond to HIV-1 binding by rapidly increased cytokine production suggesting a role of this virus-brain cell interaction in HIV-1 neuropathogenesis.

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“…Subsequently NMDA receptors (Lipton et al 1991; Savio and Levi 1993), and inflammatory cytokines (Yeung et al 1995; Westmoreland et al 1996), were shown to regulate gp120-induced neurotoxicity. In 1996, it was demonstrated that TGF-β, a protective cytokine, could decrease the toxic effect of gp120 (Meucci and Miller 1996).…”

Section: Introductionmentioning

confidence: 99%

CXCL12 Signaling in the Development of the Nervous System

Mithal

Banisadr

Miller

2012

J Neuroimmune Pharmacol

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Chemokines are small, secreted proteins that have been shown to be important regulators of leukocyte trafficking and inflammation. All the known effects of chemokines are transduced by action at a family of G protein coupled receptors. Two of these receptors, CCR5 and CXCR4, are also known to be the major cellular receptors for HIV-1. Consideration of the evolution of the chemokine family has demonstrated that the chemokine Stromal cell Derived Factor-1 or SDF1 (CXCL12) and its receptor CXCR4 are the most ancient members of the family and existed in animals prior to the development of a sophisticated immune system. Thus, it appears that the original function of chemokine signaling was in the regulation of stem cell trafficking and development. CXCR4 signaling is important in the development of many tissues including the nervous system. Here we discuss the manner in which CXCR4 signaling can regulate the development of different structures in the central and peripheral nervous systems and the different strategies employed to achieve these effects.

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The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-α

Cited by 156 publications

References 0 publications

HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood–brain barrier: modulatory effects of STAT1 signaling

HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood–brain barrier: modulatory effects of STAT1 signaling

Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection

CXCL12 Signaling in the Development of the Nervous System

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