Tripartite containing motif 32 modulates proliferation of human neural precursor cells in HIV-1 neurodegeneration

Cell Death Differ. 2016 May;23(5):776-86. doi: 10.1038/cdd.2015.138. Epub 2015 Nov 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Proliferation
  • HIV Infections / metabolism*
  • HIV Infections / pathology*
  • HIV Infections / virology
  • HIV-1 / pathogenicity*
  • Humans
  • Immunohistochemistry
  • MicroRNAs / metabolism
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology*
  • Neural Stem Cells / virology
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • MIRN155 microRNA, human
  • MicroRNAs
  • Transcription Factors
  • Tripartite Motif Proteins
  • tat Gene Products, Human Immunodeficiency Virus
  • TRIM32 protein, human
  • Ubiquitin-Protein Ligases