Neurodegenerative disorders including HIV-associated dementia (HAD) are observed in approximately 20 percent of patients with HIV infection, principally those with AIDS. Recent studies demonstrating the concordance of viral quasi-species in CNS and those in bone marrow and PBMCs, together with the neurocognitive improvements observed with HAART therapy, have suggested an important role for events occurring outside the CNS compartment in the development of HIV associated dementia. In circulation, increased numbers of CD14+/CD16+ positive monocytes have been observed in HIV infected individuals with AIDS, with even higher levels among persons with HAD. The abnormal numbers of these activated cells has been proposed to provide a mechanism for CNS invasion and neuronal injury. Our preliminary studies in CNS tissues from patients with HIV encephalitis (HIVE) demonstrate that CD14+/CD16+ macrophages accumulate in the perivascular space and in """"""""microglial"""""""" nodules. These cells appear be derived from the expanded activated monocyte subset in circulation as determined by CD45/LCA staining. In addition to the relatively transient perivascular macrophages (CD 14+/CD 16+), our preliminary studies also identify many CD14-/CD16+ mononuclear phagocytes (MPs) in areas of white matter distant from blood vessels, with a ramified morphology. Both perivascular and parenchymal mononuclear phagocytes (MPs) represent reservoirs of HIV infection in CNS. The large increases in the numbers of total perivascular and parenchymal CD68+ MPs we observed, in the absence of proliferation, support our hypothesis that abnormal monocyte/macrophage/trafficking mechanisms contribute to pathogenesis of HIV in CNS. Furthermore, we have observed increased accumulation of CD 16+ MPs, not only in brain, but in multiple organs in patients with HIVE including spleen, lymph node, kidney, and liver. In kidney, we further observe histologic evidence for underlying HIV associated nephropathy in tissue specimens from patients with HIVE. These results suggest a major role for monocyte/macrophage invasion and accumulation in the pathogenesis of AIDS in CNS as well as other organs. In our proposed studies (Specific Aim I), we will determine the relationship between macrophages in CNS, bone marrow, blood, and visceral tissues in HIVE using immunohistochemical and viral-genetic approaches. These studies will be further extended to an in vivo animal model (Specific Aim II) in SIV infected Rhesus macaques. Here we will investigate the expansion of activated monocyte/macrophages and their invasion into CNS and visceral tissue during the course of infection leading to AIDS and SIV encephalitis. We will further examine the migration of labeled autologous monocyte/macrophages into various organs and determine monocyte turnover kinetics in SIVE, SIV/AIDS, and control animals. By combining viral-genetic and tissue based studies in human specimens and in in vivo non-human primate studies, we will gain important information regarding monocyte/macrophage production, trafficking and abnormal organ accumulation in HIVE. We anticipate that these studies will provide novel concepts regarding the role of abnormal monocyte/macrophage production and trafficking in the pathogenesis of AIDS and HIVE, and provide a rationale for novel treatment strategies targeting the monocyte/macrophage developmental program, activation and/or trafficking. ? ? ? ?
