The neuropathogenesis of HIV encephalitis and HIV dementia is associated with sustained viral replication in brain macrophages and microglia. Viral penetration of the BBB and productive infection of brain macrophages appears necessary but not sufficient for the development of neurological abnormalities. Therefore, the hypothesis of interest is that specific viral neurotropic strains may produce qualitative changes in brain function resulting in macrophage effector molecule neurotoxin release. In addition, different strains of HIV-1 could produce qualitatively distinct central nervous system (CNS) abnormalities that affect monocyte transendothelial migration and production of toxins. To assess the role of specific HIV-1 strains in viral neuropathogenesis, the Investigator plans to study virologic, cellular immune, and functional outcomes of virus-macrophage interactions. Utilizing a blood/brain barrier system in the SCID mouse model of HIV encephalitis, he and his associates will propagate large numbers of microglia and blood monocytes to perform interactive experiments that could validate the hypothesis that different HIV-1 strains could produce distinct CNS pathological lesions. These studies will provide a rationale to address scientifically whether specific HIV-1 strains induce changes, qualitative and quantitative, in macrophage function that affect CNS neuroimmune interactions leading to progressive neurological disease in AIDS.
