Secretion of Neurotoxins by Mononuclear Phagocytes Infected with HIV-1

Giulian, Dana; Vaca, Ken; Noonan, Christine A.

doi:10.1126/science.2148832

Cited by 604 publications

(333 citation statements)

References 44 publications

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“…[1][2][3]7,15 This leads to toxin production by these monocytic cells, which seems essential for a pronounced neurodegenerative effect. 7,11,[16][17][18] Indeed, we and others have observed earlier that gp120 neurotoxicity was virtually absent if microglia were either removed from mixed cerebrocortical cultures or inactivated. 10,11,18,19 This finding strongly suggested a critical role for microglial HIV-1 coreceptors in the generation of neurotoxicity.…”

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confidence: 73%

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/ gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1b and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca 2 þ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca 2 þ . This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.

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confidence: 73%

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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“…Manifestations of ADC are progressive cognitive, motor, and behavioral dysfunctions that have been linked to the persistence of HIV-1 infections in the CNS and are mainly found in CD4-positive (CD4+) microglial cells and circulating macrophages (Budka, 1991;Fauci, 1988;Jordan et al, 1991;Ketzler et al, 1990;Liu et al, 1990;Maddon et al, 1986;McArthur, 1987;Merrill and Chen, 1991;Price et al, 1988). However, in the absence of CD4 molecules on the cell membrane of the majority of brain cells and in the light of the paucity of direct evidence for HIV infection of neurons and glial cells it has been suggested that the HIV-associated degenerative neurological abnormalities are the result of indirect mechanisms mediated by soluble factors of viral or cellular origin (Brenneman et a/., 1988;Dreyer et al, 1990;Giulian et al, 1990;Kaiser et al, 1990;Pulliam et al, 1991;Wahl et al, 1991 ). These factors could be cytotoxic to Subpopulations of brain cells or interfere with neuronal and glial cell functions leading to neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 gp120 receptor on CD4-negative brain cells activates a tyrosine kinase

Schneider-Schaulies¹,

Schneider‐Schaulies²,

Brinkmann³

et al. 1992

Virology

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Human immunodeficiency virus (HIV-1) infection in the human brain Ieads to characteristic neuropathological changes, which may result indirectly from interactions of the envelope glycoprotein gp 120 with neurons and/or glial cells. We therefore investigated the binding of recombinant gp120 (rgp120) to human neural cells and its effect on int~acellular.s.ignallin~. Herewe pre~ent evidence that rgp120, besides binding to galactocerebroside or galactosyl-sulfatlde, spec1f1cally bmds to a protem receptor of a relative molecular mass of approximately 180,000 Da (180 kDa) pre~ent. on the CD4-negative glioma cells D-54, but not on Molt4 T lymphocytes. Binding of rgp120 to this receptor rap1dly 1nduced a tyrosine-specific protein kinase activity leading to tyrosine phosphorylation of 130-and 115-kDa p~oteins. The c~ncentration of intracellular calciumwas not affected by rgp120 in these cells. Our data suggest a novel Signal transduc1ng HIV-1 gp120 receptor on CD4-negative glial cells, which may contribute to the neuropathological changes observed in HIV-1-infected brains.

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“…Sin embargo, ciertos estados patológicos, entre ellos la infección por el VIH-1, generan una producción no regulada de estos factores, lo que produce alteraciones en el desarrollo neurológico. En este mismo sentido, varias investigaciones recientes señalan que mediadores solubles producidos por monocitos/ macrófagos de pacientes infectados con el VIH-1, alteran el crecimiento y la supervivencia de las neuronas y de las células gliales inmaduras en cultivo (44)(45)(46). Se han documentado niveles alterados de IL-1, IL-6, TNF-a y MCP-1 en el líquido cefalorraquídeo (LCR) de pacientes con sida, tanto adultos como pediátricos (47)(48)(49).…”

Section: Mediadores Inmunológicos Y Proteínas Virales Solubles Actorunclassified

El virus de la inmunodeficiencia humana tipo 1 y el sistema nervioso central en desarrollo.

et al. 2005

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Actualmente, hay más de 42 millones de infectados con el virus de la inmunodeficiencia humana tipo 1 (VIH-1), de los cuales, 3,2 millones son niños y, de éstos, el 90% con transmisión vertical de la infección. Se considera que en Colombia más de 200.000 personas se han infectado desde el inicio de la pandemia y los estudios muestran una tendencia constante al aumento en las cifras de seroprevalencia en mujeres embarazadas y, por ende, en el número de recién nacidos infectados. El VIH-1 es primordialmente linfotrópico, pero su tropismo por el sistema nervioso central (SNC) es bien conocido, lo que genera múltiples alteraciones neurológicas, particularmente prominentes en niños, de las cuales la más prevalerte es la encefalopatía. Clásicamente, se reconocen dos tipos de encefalopatía en esta población: encefalopatía temprana y tardía, ambas con diferentes características clínicas e inmunológicas. La infección por el VIH-1 en el SNC está limitada a los macrófagos, la microglía y los astrocitos en menor escala. Las neuronas, células principalmente afectadas en los pacientes con sida, raras veces son infectadas, por lo que se postula que factores solubles, provenientes tanto del huésped como del virus, son los principales causantes del daño neuronal. Los hallazgos presentados en esta revisión sugieren la posibilidad de que el SNC, en etapas tempranas del desarrollo, sea especialmente susceptible a la infección por el VIH-1. Las cifras epidemiológicas sugieren que este tipo de alteraciones clínicas serán cada vez más frecuentes; de ahí, la importancia de conocer la neuropatogénesis de la infección por el VIH-1.Palabras clave: encefalitis, VIH-1, neuropatogénesis, neurogénesis, citocinas, embriología. The human immunodeficiency virus type 1 and the developing central nervous systemCurrently, at least 42 million people are infected worldwide with the human immunodeficiency virus type 1 (HIV-1). Of these, 3.2 million are children infected, in 90% of the cases, through vertical transmission. In Colombia, approximately 200,000 persons have been infected since the beginning of the pandemic, with an increasing trend in the seroprevalence among pregnant women. Although HIV-1 is basically lymphotropic, its capacity to invade the central nervous system (CNS) is well known, generating multiple neurological alterations, especially prominent in children, with encephalopathy being the most prevalent. Classically, two types of neurological disorders are recognized in children, consisting of early and late encephalopathies, each with differing clinical and immunological characteristics. HIV-1 infection of the CNS is limited to macrophages, microglia and astrocytes in a restricted manner. In patients with acquired immunodeficiency virus (AIDS), neurons are rarely infected, suggesting that cellular and viral soluble factors, are responsible for the neuronal damage. The conclusion is that the CNS in earlier stages of development is especially susceptible to HIV-1 infection. The epidemiological trends predict that these types of clinical...

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Secretion of Neurotoxins by Mononuclear Phagocytes Infected with HIV-1

Cited by 604 publications

References 44 publications

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

HIV-1 gp120 receptor on CD4-negative brain cells activates a tyrosine kinase

El virus de la inmunodeficiencia humana tipo 1 y el sistema nervioso central en desarrollo.

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