title: Tripartite containing motif 32 modulates proliferation of human neural precursor cells in HIV-1 neurodegeneration.
abstract: In addition to glial cells, HIV-1 infection occurs in multipotent human neural precursor cells (hNPCs) and induces quiescence in NPCs. HIV-1 infection of the brain alters hNPC stemness, leading to perturbed endogenous neurorestoration of the CNS following brain damage by HIV-1, compounding the severity of dementia in adult neuroAIDS cases. In pediatric neuroAIDS cases, HIV-1 infection of neural stem cell can lead to delayed developmental milestones and impaired cognition. Using primary cultures of human fetal brain-derived hNPCs, we gained novel insights into the role of a neural stem cell determinant, tripartite containing motif 32 (TRIM32), in HIV-1 Tat-induced quiescence of NPCs. Acute HIV-1 Tat treatment of hNPCs resulted in proliferation arrest but did not induce differentiation. Cellular localization and levels of TRIM32 are critical regulators of stemness of NPCs. HIV-1 Tat exposure increased nuclear localization and levels of TRIM32 in hNPCs. The in vitro findings were validated by studying TRIM32 localization and levels in frontal cortex of HIV-1-seropositive adult patients collected at post mortem as well as by infection of hNPCs by HIV-1. We observed increased percentage of cells with nuclear localization of TRIM32 in the subventricular zone (SVZ) as compared with age-matched controls. Our quest for probing into the mechanisms revealed that TRIM32 is targeted by miR-155 as downregulation of miR-155 by HIV-1 Tat resulted in upregulation of TRIM32 levels. Furthermore, miR-155 or siRNA against TRIM32 rescued HIV-1 Tat-induced quiescence in NPCs. Our findings suggest a novel molecular cascade involving miR-155 and TRIM32 leading to HIV-1 Tat-induced attenuated proliferation of hNPCs. The study also uncovered an unidentified role for miR-155 in modulating human neural stem cell proliferation, helping in better understanding of hNPCs and diseased brain.
authors.affiliation: Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar (Gurgaon), Haryana, India.
authors.forename: M
authors.initials: M
authors.lastname: Fatima
authors.affiliation: Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar (Gurgaon), Haryana, India.
authors.forename: R
authors.initials: R
authors.lastname: Kumari
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts-Fourneaux, L-4362, Campus Belval, Esch-sur-Alzette, Luxembourg.
authors.forename: J C
authors.initials: JC
authors.lastname: Schwamborn
authors.affiliation: Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore, India.
authors.forename: A
authors.initials: A
authors.lastname: Mahadevan
authors.affiliation: Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Shankar
authors.affiliation: Laboratory of Virology, National Institute of Immunology, New Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Raja
authors.affiliation: Cellular and Molecular Neuroscience, National Brain Research Centre, Manesar (Gurgaon), Haryana, India.
authors.forename: P
authors.initials: P
authors.lastname: Seth
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D014157:Transcription Factors / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases