HIV‐1‐infected and/or immune‐activated macrophage‐secreted TNF‐α affects human fetal cortical neural progenitor cell proliferation and differentiation

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Abstract
Neurogenesis, tied to the proliferation, migration and differentiation of neural progenitor cells (NPC) is affected during neurodegenerative diseases, but how neurogenesis is affected during HIV‐1 associated dementia (HAD) has not been fully addressed. Here we test the hypothesis that HIV‐1‐infected and/or immune‐activated brain macrophages affect NPC proliferation and differentiation through the regulation of cytokines. We showed that human monocyte‐derived macrophages (MDM) conditioned medium (MCM) induces a dose dependant increase in NPC proliferation. Conditioned media from lipopolysaccharide (LPS)‐activated MDM (LPS‐MCM) or HIV‐infected MCM (HIV‐MCM) induced a profound increase in NPC proliferation. HIV‐infected and LPS‐activated MCM (HIV+LPS‐MCM) induced the most robust increase in NPC proliferation. Moreover, LPS‐MCM and HIV+LPS‐MCM decreased β‐III‐tubulin and increased GFAP expression, demonstrating an induction of gliogenesis and inhibition of neurogenesis. The increase of NPC proliferation and gliogenesis correlated with increases in production of TNF‐α by infected/activated MDM. Although both IL‐1β and TNF‐α induced NPC proliferation and gliogenesis, these effects were only partially abrogated by soluble TNF‐α receptors R1 and R2 (TNF‐R1R2), but not by the IL‐1 receptor antagonist (IL‐1ra). This indicated that the HIV‐1‐infected/LPS‐activated MCM‐mediated effects were, in part, through TNF‐α. These observations were confirmed in severe combined immunodeficient (SCID) mice with HIV‐1 encephalitis (HIVE). In these HIVE mice, NPC injected with HIV‐infected MDM showed more astrocyte differentiation and less neuronal differentiation compared to NPC injection alone. These observations demonstrated that HIV‐1‐infected and immune‐activated MDM could affect neurogenesis through induction of NPC proliferation, inhibition of neurogenesis, and activation of gliogenesis.