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Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia

Y Persidsky1, J Zheng, D Miller

  • 1Center for Neurovirology and Neurodegenerative Disorders, the Department of Pathology, University of Nebraska Medical Center, Omaha 68198-5215, USA. ypersids@unmc.edu

Journal of Leukocyte Biology
|September 14, 2000
PubMed

Insights

HIV-1 infection causes brain immune cells to release chemokines, which contribute to HIV-1 encephalitis and dementia by affecting brain cells and neuron function.

Area of Science:

  • Neuroscience
  • Immunology
  • Virology

Background:

  • HIV-1 neuropathogenesis involves immune-activated brain mononuclear phagocytes (MP) producing secretory factors.
  • MP-secreted chemokines are implicated in HIV-1 encephalitis (HIVE), potentially promoting macrophage infiltration and blood-brain barrier (BBB) dysfunction.

Purpose of the Study:

  • To investigate how HIV-1-infected MP regulate chemokine production.
  • To understand the influence of these chemokines on HIV-1 neuropathogenesis and HIV-1-associated dementia.

Main Methods:

  • Laboratory assays and analysis of infected brain tissue to assess chemokine production by HIV-1-infected MP (microglia, astrocytes).
  • Utilizing a BBB model system and SCID mice with HIVE to evaluate the impact of HIV-1-infected microglia on monocyte migration.
  • Examining human autopsy brain tissue and SCID mice with HIVE to assess effects on brain microvascular endothelial cells and tight junction proteins.

Main Results:

  • HIV-1-infected and immune-activated MP, including microglia and astrocytes, were found to produce abundant beta-chemokines.
  • HIV-1-infected microglia significantly altered monocyte migration in both BBB models and HIVE models in SCID mice.
  • HIV-1-infected MP were shown to down-regulate tight junction proteins and polarized transport systems in brain microvascular endothelial cells.

Conclusions:

  • Chemokines play diverse and significant roles in HIV-1 neuropathogenesis, contributing to BBB dysfunction and neuronal damage.
  • The binding of chemokines like stromal-derived factor-1alpha to neuronal receptors can directly cause neurotoxicity.
  • These findings provide a foundation for developing future therapeutic strategies targeting chemokine pathways in HIV-1-associated neurological disorders.

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