Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia.
The neuropathogenesis of HIV-1 infection revolves around the production of secretory factors from immune-activated brain mononuclear phagocytes (MP). MP-secreted chemokines may play several roles in HIV-1 encephalitis (HIVE). These can promote macrophage brain infiltration, blood-brain barrier (BBB) and neuronal dysfunction during HIV-1-associated dementia. We investigate how HIV-1-infected MP regulates the production of chemokines and how they influence HIV-1 neuropathogenesis. We demonstrate that HIV-1-infected and immune-activated MP (for example, microglia) and astrocytes produce beta-chemokines in abundance, as shown in both laboratory assays and within infected brain tissue. HIV-1-infected microglia significantly modulate monocyte migration in a BBB model system and in brains of SCID mice with HIVE. HIV-1-infected MP down-regulate tight junction protein and special polarized transport systems on brain microvascular endothelial cells as shown in human autopsy brain tissue and in SCID mice with HIVE. Chemokines can damage neurons directly. Toxicity caused by binding of stromal-derived factor-1alpha to its receptor on neurons exemplifies such mechanism. In toto, these works underscore the diverse roles of chemokines in HIV-1 neuropathogenesis and lay the foundation for future therapeutic interventions.
Persidsky
Y
Y
Center for Neurovirology and Neurodegenerative Disorders, the Department of Pathology, University of Nebraska Medical Center, Omaha 68198-5215, USA. ypersids@unmc.edu
Zheng
J
J
Miller
D
D
Gendelman
H E
HE
D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000473:pathology / Q000821:virology*; D015497:HIV-1; D006801:Humans; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000473:pathology / Q000821:virology*; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*