Mononuclear phagocytes mediate blood-brain barrier compromise and neuronalinjury 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 i nfluence HIV-1 neuropathogenesis. We demonstrate that HIV-1-infected and im mune-activated MP (for example, microglia) and astrocytes produce beta-chem okines in abundance, as shown in both laboratory assays and within infected brain tissue, HIV-1-infected microglia significantly modulate monocyte mig ration in a BBB model system and in brains of SCID mice with HIVE. HIV-1-in fected MP down-regulate tight junction protein and special polarized transp ort systems on brain microvascular endothelial cells as shown in human auto psy brain tissue and in SCID mice with HIVE. Chemokines can damage neurons directly. Toxicity caused by binding of stromal-derived factor-1 alpha to i ts receptor on neurons exemplifies such mechanism. In toto, these works und erscore the diverse roles of chemokines in HIV-1 neuropathogenesis and lay the foundation for future therapeutic interventions.