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Increased Microglial CSF1R Expression in the SIV/Macaque Model of HIV CNS Disease

Audrey C Knight1, Samuel A Brill1, Suzanne E Queen1

  • 1Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Journal of Neuropathology and Experimental Neurology
|January 11, 2018
PubMed

Insights

Chronic microglial activation drives neuroinflammation in HIV CNS disease. Colony stimulating factor 1 receptor (CSF1R) signaling is upregulated in SIV-infected macaques, indicating its role in disease progression.

Area of Science:

  • Neuroimmunology
  • Neurovirology
  • Cellular signaling

Background:

  • Chronic microglial activation and neuroinflammation are central to neurodegenerative diseases, including HIV-associated neurocognitive disorders.
  • Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for myeloid cell function and is implicated in other neurodegenerative conditions like ALS and Alzheimer's disease.
  • CSF1R inhibition has shown therapeutic benefits in animal models of neurodegeneration.

Purpose of the Study:

  • To investigate the role of Colony stimulating factor 1 (CSF1) and Colony stimulating factor 1 receptor (CSF1R) signaling in the central nervous system (CNS) during Simian Immunodeficiency Virus (SIV) infection, a model for HIV CNS disease.
  • To determine if CSF1R is expressed in microglia and if its expression is altered in SIV-infected macaques.

Main Methods:

  • Utilized a SIV/macaque model of HIV CNS disease.
  • Employed Nanostring nCounter immune panel for gene expression analysis.
  • Performed in situ hybridization to localize CSF1R mRNA.
  • Quantified CSF1R protein levels using ELISA and immunostaining with digital image analysis.

Main Results:

  • Central nervous system (CNS) expression of Colony stimulating factor 1 (CSF1) was significantly increased in SIV-infected macaques.
  • CSF1 overexpression correlated with upregulated microglial genes involved in antiviral and oxidative stress responses.
  • CSF1R mRNA was exclusively detected in Iba-1 positive microglia.
  • SIV-infected macaques, both untreated and on suppressive antiretroviral therapy (ART), exhibited significantly elevated CSF1R levels in the frontal cortex compared to uninfected controls.

Conclusions:

  • Coordinate upregulation of CSF1 and CSF1R expression is implicated in the pathogenesis of progressive HIV CNS disease.
  • The CSF1R signaling pathway represents a potential therapeutic target for managing neuroinflammation in HIV CNS disorders.
  • Persistent elevation of CSF1R, even with ART, suggests ongoing microglial activation and neuroinflammatory processes in HIV CNS disease.
Keywords:
Colony stimulating factor 1 (CSF1)Colony stimulating factor 1 receptor (CSF1R)Human immunodeficiency virus (HIV)MacaqueMicrogliaNeurodegenerationSimian immunodeficiency virus (SIV)

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