Systemic HIV-1 infection produces a unique glial footprint in humanized mouse brains

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Abstract

Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are limited by a dearth of human disease-relevant small-animal models. To overcome this obstacle, newborn NOD/SCID/IL2Rγc-/- (NSG) mice were reconstituted with a humanized brain and immune system. NSG animals of both sexes were transplanted with human neuroglial progenitor cells (NPCs) and hematopoietic stem cells. Intraventricular injection of NPCs symmetrically repopulated the mouse brain parenchyma with human astrocytes and oligodendrocytes. Human glia were in periventricular areas, white matter tracts, the olfactory bulb and the brain stem. HIV-1 infection led to meningeal and perivascular human leukocyte infiltration into the brain. Species-specific viralneuroimmune interactionswere identified by deepRNA sequencing. In the corpus callosum and hippocampus of infected animals, overlapping human-specific transcriptional alterations for interferon type 1 and 2 signaling pathways (STAT1, STAT2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) were observed. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG, ZNF488) were downregulated. The data sets were confirmed by real-time PCR. These viral defense-signaling patterns paralleled neuroimmune communication networks seen in HIV-1-infected human brains. In this manner, this new mousemodel of neuroAIDS can facilitate diagnostic, therapeutic and viral eradication strategies for an infected nervous system.

Original languageEnglish (US)
Pages (from-to)1489-1502
Number of pages14
JournalDMM Disease Models and Mechanisms
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Neuroglia
HIV Infections
HIV-1
Brain
Animals
Oligodendroglia
Interferon Type I
Immune system
Stem Cells
Neurology
Stem cells
Viruses
Intraventricular Injections
Infiltration
Telecommunication networks
Antiviral Agents
Corpus Callosum
Olfactory Bulb
Myelin Sheath
Hematopoietic Stem Cells

Keywords

  • Astrocytes
  • HIV-1
  • Hematopoietic stem progenitor cells
  • Humanized mice
  • Neuronal progenitors

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "Systemic HIV-1 infection produces a unique glial footprint in humanized mouse brains",
abstract = "Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are limited by a dearth of human disease-relevant small-animal models. To overcome this obstacle, newborn NOD/SCID/IL2Rγc-/- (NSG) mice were reconstituted with a humanized brain and immune system. NSG animals of both sexes were transplanted with human neuroglial progenitor cells (NPCs) and hematopoietic stem cells. Intraventricular injection of NPCs symmetrically repopulated the mouse brain parenchyma with human astrocytes and oligodendrocytes. Human glia were in periventricular areas, white matter tracts, the olfactory bulb and the brain stem. HIV-1 infection led to meningeal and perivascular human leukocyte infiltration into the brain. Species-specific viralneuroimmune interactionswere identified by deepRNA sequencing. In the corpus callosum and hippocampus of infected animals, overlapping human-specific transcriptional alterations for interferon type 1 and 2 signaling pathways (STAT1, STAT2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) were observed. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG, ZNF488) were downregulated. The data sets were confirmed by real-time PCR. These viral defense-signaling patterns paralleled neuroimmune communication networks seen in HIV-1-infected human brains. In this manner, this new mousemodel of neuroAIDS can facilitate diagnostic, therapeutic and viral eradication strategies for an infected nervous system.",
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author = "Weizhe Li and Santhi Gorantla and Gendelman, {Howard Eliot} and Poluektova, {Larisa Y}",
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AU - Gorantla, Santhi

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