title: CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120.
abstract: The innate immune system has been implicated in several neurodegenerative diseases, including HIV-1-associated dementia. In this study, we show that genetic ablation of CCR5 prevents microglial activation and neuronal damage in a transgenic model of HIV-associated brain injury induced by a CXCR4-using viral envelope gp120. The CCR5 knockout (KO) also rescues spatial learning and memory in gp120-transgenic mice. However, the CCR5KO does not abrogate astrocytosis, indicating it can occur independently from neuronal injury and behavioral impairment. To characterize further the neuroprotective effect of CCR5 deficiency we performed a genome-wide gene expression analysis of brains from HIVgp120tg mice expressing or lacking CCR5 and nontransgenic controls. A comparison with a human brain microarray study reveals that brains of HIVgp120tg mice and HIV patients with neurocognitive impairment share numerous differentially regulated genes. Furthermore, brains of CCR5 wild-type and CCR5KO gp120tg mice express markers of an innate immune response. One of the most significantly upregulated factors is the acute phase protein lipocalin-2 (LCN2). Using cerebrocortical cell cultures, we find that LCN2 is neurotoxic in a CCR5-dependent fashion, whereas inhibition of CCR5 alone is not sufficient to abrogate neurotoxicity of a CXCR4-using gp120. However, the combination of pharmacologic CCR5 blockade and LCN2 protects neurons from toxicity of a CXCR4-using gp120, thus recapitulating the finding in CCR5-deficient gp120tg mouse brain. Our study provides evidence for an indirect pathologic role of CCR5 and a novel protective effect of LCN2 in combination with inhibition of CCR5 in HIV-associated brain injury.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Ricky
authors.initials: R
authors.lastname: Maung
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Hoefer
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanchez
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Natalia E
authors.initials: NE
authors.lastname: Sejbuk
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Medders
authors.affiliation: Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Maya K
authors.initials: MK
authors.lastname: Desai
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Irene C
authors.initials: IC
authors.lastname: Catalan
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Cari C
authors.initials: CC
authors.lastname: Dowling
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
authors.forename: Cyrus M
authors.initials: CM
authors.lastname: de Rozieres
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195;
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.affiliation: Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; Department of Pharmacobiology, University of Calabria, 87036 Arcavacata di Rende, Italy;
authors.forename: Rossella
authors.initials: R
authors.lastname: Russo
authors.affiliation: Molecular and Cellular Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: Bioinformatics Shared Resource, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and.
authors.forename: Roy
authors.initials: R
authors.lastname: Williams
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093 mkaul@sanfordburnham.org.
authors.forename: Marcus
authors.initials: M
authors.lastname: Kaul
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics*; D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005911:Gliosis; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015497:HIV-1; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis / Q000378:metabolism*; D018782:Maze Learning; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000209:Acute-Phase Proteins; D065100:CCR5 Receptor Antagonists; C514936:CXCR4 protein, mouse; D015699:HIV Envelope Protein gp120; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1; C071332:Lcn2 protein, mouse