AIDS patients and mice expressing the envelope glycoprotein gp120 of human immunodeficiency virus-1 (HIV-1) as transgene in the brain (gp120tg) share key features of viral neuropathology, such as a decrease of neurites and synapses, pronounced astrocytosis and activated microglia and macrophages. Virus-associated or soluble HIV-1 gp120 interacts with CD4 and co-receptors CCR5 and CXCR4 leading to infection and/or cellular signaling. In the present study we crossed HIVgp120tg with CCR5KO mice. Microarray analysis of brain tissue from 6 month-old mice showed that HIV-1 gp120 affected the expression of about 800 genes in the presence of CCR5 but of only 51 genes in the absence of the co-receptor. Differentially expressed genes in CCR5 wild type (wt)/gp120tg mice compared to non-transgenic controls primarily belong in the nervous and immune systems. CCR5KO/gp120tg mice and non-transgenic CCR5KO controls differed mostly in expression of an astrocytic protein and factors of the innate immune system. Using quantitative fluorescence and deconvolution microscopy, we assessed neuronal injury and glial cell activation in brain sections. CCR5wt/gp120tg mice displayed a significant reduction in neuronal dendrites and pre-synaptic terminals besides microglial activation (increased Iba1 immuno-reactivity) in comparison to all of the three other genotypes. Thus, in our model CCR5 is required for HIV-1 gp120 to activate microglia and to cause damage to neuronal processes and synapses

CCR5-deficiency abrogates microglial activation and neuronal injury in HIV gp120-transgenic mice

RUSSO, Rossella;
2012-01-01

Abstract

AIDS patients and mice expressing the envelope glycoprotein gp120 of human immunodeficiency virus-1 (HIV-1) as transgene in the brain (gp120tg) share key features of viral neuropathology, such as a decrease of neurites and synapses, pronounced astrocytosis and activated microglia and macrophages. Virus-associated or soluble HIV-1 gp120 interacts with CD4 and co-receptors CCR5 and CXCR4 leading to infection and/or cellular signaling. In the present study we crossed HIVgp120tg with CCR5KO mice. Microarray analysis of brain tissue from 6 month-old mice showed that HIV-1 gp120 affected the expression of about 800 genes in the presence of CCR5 but of only 51 genes in the absence of the co-receptor. Differentially expressed genes in CCR5 wild type (wt)/gp120tg mice compared to non-transgenic controls primarily belong in the nervous and immune systems. CCR5KO/gp120tg mice and non-transgenic CCR5KO controls differed mostly in expression of an astrocytic protein and factors of the innate immune system. Using quantitative fluorescence and deconvolution microscopy, we assessed neuronal injury and glial cell activation in brain sections. CCR5wt/gp120tg mice displayed a significant reduction in neuronal dendrites and pre-synaptic terminals besides microglial activation (increased Iba1 immuno-reactivity) in comparison to all of the three other genotypes. Thus, in our model CCR5 is required for HIV-1 gp120 to activate microglia and to cause damage to neuronal processes and synapses
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/180230
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