Neuropathologic and neuroinflammatory activities of HIV-1-infected human astrocytes in murine brain

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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 thisinfection 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.