Neuropathologic and neuroinflammatory activities of HIV-1-infected human astrocytes in murine brain.
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.
Dou
Huanyu
H
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
Morehead
Justin
J
Bradley
Jennifer
J
Gorantla
Santhi
S
Ellison
Brent
B
Kingsley
Jeff
J
Smith
Lynette M
LM
Chao
Wei
W
Bentsman
Galina
G
Volsky
David J
DJ
Gendelman
Howard E
HE
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