Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia

Sci Rep. 2020 Sep 16;10(1):15209. doi: 10.1038/s41598-020-72214-0.

Abstract

HIV-1 associated neurocognitive disorder (HAND) is characterized by neuroinflammation and glial activation that, together with the release of viral proteins, trigger a pathogenic cascade resulting in synaptodendritic damage and neurodegeneration that lead to cognitive impairment. However, the molecular events underlying HIV neuropathogenesis remain elusive, mainly due to lack of brain-representative experimental systems to study HIV-CNS pathology. To fill this gap, we developed a three-dimensional (3D) human brain organoid (hBORG) model containing major cell types important for HIV-1 neuropathogenesis; neurons and astrocytes along with incorporation of HIV-infected microglia. Both infected and uninfected microglia infiltrated into hBORGs resulting in a triculture system (MG-hBORG) that mirrors the multicellular network observed in HIV-infected human brain. Moreover, the MG-hBORG model supported productive viral infection and exhibited increased inflammatory response by HIV-infected MG-hBORGs, releasing tumor necrosis factor (TNF-α) and interleukin-1 (IL-1β) and thereby mimicking the chronic neuroinflammatory environment observed in HIV-infected individuals. This model offers great promise for basic understanding of how HIV-1 infection alters the CNS compartment and induces pathological changes, paving the way for discovery of biomarkers and new therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / cytology*
  • Brain / metabolism
  • Brain / pathology
  • Brain / virology
  • Cell Differentiation
  • Culture Media / chemistry
  • HEK293 Cells
  • HIV Infections / complications*
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV-1 / pathogenicity*
  • Humans
  • Interleukin-1beta / metabolism
  • Models, Anatomic
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neural Stem Cells / virology
  • Neurocognitive Disorders / etiology
  • Neurocognitive Disorders / metabolism
  • Neurocognitive Disorders / pathology*
  • Organ Culture Techniques
  • Organoids / cytology*
  • Organoids / metabolism
  • Organoids / pathology
  • Organoids / virology
  • Tumor Necrosis Factor-alpha / metabolism
  • Virus Replication

Substances

  • Culture Media
  • IL1B protein, human
  • Interleukin-1beta
  • TNF protein, human
  • Tumor Necrosis Factor-alpha