CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice

• Published in: Molecular neurodegeneration 2021-11, Vol.16 (1), p.78-23, Article 78
• Main Authors: Bhargavan, Biju, Woollard, Shawna M, McMillan, Jo Ellyn, Kanmogne, Georgette D
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Advanced glycosylation end products; Advertising executives; AIDS; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid-beta; Amyloidogenesis; Amyloidosis; Analysis; Animals; Antibodies; Antiretroviral drugs; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-brain barrier injury; Brain damage; CCR5 protein; CD4 antigen; Chemokines; Cognition; Endothelial cells; Endothelial Cells - metabolism; Enzyme-linked immunosorbent assay; Enzymes; Flow cytometry; Glycosylation; Histocompatibility antigen HLA; HIV; HIV (Viruses); HIV infection; HIV patients; HIV-1; Human immunodeficiency virus; Immune system; Immunoblotting; Immunofluorescence; Immunohistochemistry; Infection; Infections; Infiltration; Injuries; Interleukin 2 receptors; Laboratory animals; Leukocytes; Low density lipoproteins; Lymphocytes T; Macrophages; Maraviroc; Mice; Mice, Inbred NOD; Neurodegeneration; Neurodegenerative diseases; Neuronal damage; Neurons; NSG mice; Phosphorylation; Plasma; Prevention; Proteins; Receptor density; Receptor for Advanced Glycation End Products - metabolism; Secretase; T cells; Tau phosphorylation; Transcription; Virus diseases
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-021-00500-0

Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer's Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies. NOD/scid-IL-2Rγ mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal's blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA. HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor-related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist. Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular