AN ANALYSIS OF HIV-1-ASSOCIATED INFLAMMATORY PRODUCTS IN BRAIN-TISSUEOF HUMANS AND SCID MICE WITH HIV-1 ENCEPHALITIS

The human immunodeficiency virus type 1 (HIV)-associated dementia comp lex (ADC) is a neuroimmunological disorder fueled by viral replication ire mononuclear phagocytes (MP) (brain macro]phages and microglia). T he elucidation of MP inflammatory factors involved in neurological dys function is pivotal for unraveling pathogenic mechanisms and in develo ping new a therapies for this disease. Recent advances in animal model systems for ADC and its associated encephalitis have provided importa nt insights into how virus-infected macrophages cause brain injury. In deed, the stereotactic inoculation of HIV infected monocytes into the basal ganglia/cortex of mice with severe combined immunodeficiency dis ease (SCID) results in pathological features similar to those of human HIV-1 encephalitis (HIVE). We used this SCID model to study the roles of macrophage secretory factors in HIVE. The expression of interleuki n-1 (IL-1 beta, IL-6, IL-10), tumor necrosis factor-alpha (TNF alpha), vascular endothelial growth factor (VEGF), and adhesion molecules (E- selectin, intracellular cell adhesion molecule (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1)) in encephalitic brains of mice and humans was evaluated by semi-quantitative polymerase chain reaction (P CR). In SCID mice with HIVE, human and mouse TNF alpha, and mouse IL-6 , VEGF, VCAM-1 and E-selectin were expressed at high levels. These res ults paralleled, to a great extent, those in HIVE brain tissues. Laser scanning confocal microscopy performed to assess the associated neuro nal damage showed that microtubule associated protein-2 (MAP-2) immuno reactive dendrites were significantly reduced in both the ipsilateral and contralateral hemispheres of encephalitic mice. These results demo nstrate the importance of macrophage inflammatory products in the path ogenesis of HIVE and further validates this model of viral encephaliti s in SCID mice.