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* Center for Neurovirology and Neurodegenerative Disorders, the Departments of
Pathology and Microbiology,
Medicine,
The Eppley Institute for Cancer and Allied Diseases, and
|| College of Pharmacy, University of Nebraska Medical Center, Omaha
Correspondence: Yuri Persidsky, M.D., Ph.D., Center for Neurovirology and Neurodegenerative Disorders, 985215 Nebraska Medical Center, Omaha, NE 68198-5215. E-mail: ypersids{at}unmc.edu
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
ß-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-1
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.
Key Words: chemokine • chemokine receptor • endothelial cell • microglia • astrocyte • tight junction
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