Chronic Intrahippocampal Infusion of HIV-1 Neurotoxic Proteins: A Novel Mouse Model of HIV-1 Associated Inflammation and Neural Stem Cell Dysfunction

AbstractHIV-1 infection causes chronic neuroinflammation resulting in cognitive decline associated with diminution of survival of neural stem cells (NSC). In part, this is attributable to production of toxic viral proteins (gp120 and tat) by infected cells in the brain that can activate microglia. Here, we evaluated a novel model for HIV-1 neuropathogenesis by direct administration of viral proteins into the hippocampus. Chronic administration of either HIV-1 gp120 or tat over 14  days significantly decreased NSC proliferation, survival and neuroblast formation (by 32–37%) within the hippocampal subgranular zone as detected by doublecortin/BrdU or Ki67-positive cells. Intrahippocampal administration of gp120 or tat induced microglial activation within the hippocampus as d etermined by increases in microglial number and increases in the volume of the microglia (2.5–3-fold, evaluated by double IBA-1/CD68 staining). We further assessed inflammatory responses within the hippocampus by RNAseq and Ingenuity Pathway Analysis. There was a significant mRNA upregulation of n umerous inflammatory mediators including Il1b, Icam1, Il12a, Ccl2, and Ccl4. These data suggest that chronic administration induces a prolonged inflammatory state within the hippocampus that negatively affects NSC survival potentially leading to cognitive dysfunction.Graphical Abstract
Source: Journal of NeuroImmune Pharmacology - Category: Drugs & Pharmacology Source Type: research