6-chloro-2--3--dideoxyguanosine and Encephalitis--Viral

Existing data concerning the role of the delta-chemokine fractalkine (CX3CL1) and its receptor (CX3CR1) in lentivirus-induced encephalitis are limited and controversial. We explored, by quantitative in situ hybridization and immunohistochemistry, the cell-specific changes of CX3CL1 and CX3CR1 in rhesus macaque brain during simian immunodeficiency virus (SIV) infection and antiretroviral treatment. Neuronal expression of CX3CL1 was significantly reduced in cortex and striatum of AIDS-diseased monkeys as compared with uninfected and asymptomatic SIV-infected monkeys. CX3CL1 mRNA was increased in some endothelial cells and newly induced in astrocytes and macrophages focally in areas of SIV burden and inflammatory infiltrates. In most CX3CL1-positive astrocytes and macrophages, the transcription factor NF-kappaB was translocated to the nucleus. CX3CR1 was upregulated in scattered, nodule, and giant cell-forming microglia/macrophages and mononuclear infiltrates close to CX3CL1-induced cells in the brain. Treatment of AIDS monkeys with the central nervous system-permeant 6-chloro-2',3'-dideoxyguanosine fully reversed SIV burden, productive inflammation, nuclear NF-kappaB translocation as well as focal induction of CX3CL1 in astrocytes and macrophages and downregulation in neurons. In contrast, diffuse CX3CR1-positive microgliosis and GFAP-positive astrogliosis were partially reversed by 6-chloro-2',3'-dideoxyguanosine. Thus, focally induced CX3CL1 may be a target for therapeutic intervention to limit ongoing inflammatory infiltration into brain in lentivirus infection.

Topics: Active Transport, Cell Nucleus; Animals; Anti-Retroviral Agents; Astrocytes; Brain; Chemokine CX3CL1; Chemokines, CX3C; Chemotaxis, Leukocyte; CX3C Chemokine Receptor 1; Dideoxynucleosides; Disease Models, Animal; Disease Progression; Encephalitis, Viral; Endothelial Cells; Gene Expression Regulation; Gliosis; Immunohistochemistry; In Situ Hybridization; Macaca mulatta; Macrophages; Membrane Proteins; NF-kappa B; Receptors, Chemokine; RNA, Messenger; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Treatment Outcome; Viral Load