The neuroimmune events leading to human immunodeficiency virus (HIV)-1-associated dementia (HAD) are linked to macrophage secretory neurotoxins (cellular and viral toxins). To study such events, we developed a murine model of HIV-1 encephalitis (HIVE), the pathological equivalent of HAD. Severe combined immunodeficient (SCID) mice injected with HIV-1-infected monocyte-derived macrophages (MDMs) into basal ganglia exhibited many of the pathological features of human HIVE. Moreover, behavioral and cognitive abnormalities in the HIVE mice were associated with neuronal dysfunction and decreased synaptic density. Thus, the rationale for testing novel therapeutic approaches (anti-inflammatory, antiretroviral, or neuroprotective) in the HIVE SCID mice is clear. Animals treated with anti-inflammatory compounds (platelet-activating factor [PAF] antagonist and tumor necrosis factor [TNF]-alpha release inhibitor) showed a marked reduction in brain inflammation and a reduction in neuronal injury. Comparative analyses of highly active antiretroviral therapy (HAART) regimens provided direction for which one might be most efficient for reduction of viral load in infected brain tissue. Moreover, modifications of the HIVE model might serve as a vehicle for testing vaccine approaches. Reconstitution of immunodeficient animals with syngeneic T lymphocytes followed by injection of HIV-1-infected MDMs in the brain resulted in cytotoxic antivirus T lymphocyte (CTL) response. CD8-positive T cells migrated to the sites of human MDMs, leading to the cell-mediated destruction of HIV-1 infected MDMs. These results, taken together, strongly support the use of HIVE SCID mouse model as a novel system for studies of the neuropathogenesis of HIV-1 infection, as well as for testing novel therapeutic and vaccine interventions for human disease.