title: Neuropathologic and neuroinflammatory activities of HIV-1-infected human astrocytes in murine brain.
abstract: The balance between astrocyte and microglia neuroprotection and neurotoxicity defines the tempo of neuronal dysfunction during HIV-1-associated dementia (HAD). Astrocytes maintain brain homeostasis and respond actively to brain damage by providing functional and nutritive neuronal support. In HAD, low-level, continuous infection of astrocytes occurs, but the functional consequences of this infection are poorly understood. To this end, human fetal astrocytes (HFA) and monocyte-derived macrophages (MDM) were infected with HIV-1DJV and HIV-1NL4-3 (neurotropic and lymphotropic strains respectively) and a pseudotyped Vesicular Stomatitis Virus (VSV/HIV-1NL4-3) prior to intracranial injection into the basal ganglia of severe combined immunodeficient mice. Neuropathological and immunohistochemical comparisons for inflammatory and neurotoxic activities were performed amongst the infected cell types at 7 or 14 days. HIV-1-infected MDM induced significant increases in Mac-1, glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1, and proinflammatory cytokine RNA and/or protein expression when compared with HSV/HIV-1- and HIV-1-infected HFA and sham-operated mice. Levels of neuron-specific nuclear protein, microtubule-associated protein 2, and neurofilament antigens were reduced significantly in the brain regions injected with human MDM infected with HIV-1DJV or VSV/HIV-1. We conclude that HIV-1 infection of astrocytes leads to limited neurodegeneration, underscoring the early and active role of macrophage-driven neurotoxicity in disease.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Dou
authors.forename: Justin
authors.initials: J
authors.lastname: Morehead
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bradley
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.forename: Brent
authors.initials: B
authors.lastname: Ellison
authors.forename: Jeff
authors.initials: J
authors.lastname: Kingsley
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Smith
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.forename: Galina
authors.initials: G
authors.lastname: Bentsman
authors.forename: David J
authors.initials: DJ
authors.lastname: Volsky
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002478:Cells, Cultured; D005333:Fetus; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID