Modulation of innate immunity by copolymer-1 leads to neuroprotection in murine HIV-1 encephalitis

• Published in: Glia 2008-01, Vol.56 (2), p.223-232
• Main Authors: Gorantla, Santhi, Liu, Jianuo, Wang, Tong, Holguin, Adelina, Sneller, Hannah M., Dou, Huanyu, Kipnis, Jonathan, Poluektova, Larisa, Gendelman, Howard E.
• Format: Article
• Language: English
• Subjects: Animals; anti-inflammatory; Apoptosis - drug effects; Cell Survival - drug effects; Cells, Cultured; copolymer-1; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Encephalitis, Viral - etiology; Encephalitis, Viral - pathology; Encephalitis, Viral - prevention & control; Gene Expression Regulation, Viral - drug effects; Glatiramer Acetate; Glial Fibrillary Acidic Protein - metabolism; HIV encephalitis; HIV Infections - complications; human immunodeficiency virus; Humans; Immunity, Innate - drug effects; Immunity, Innate - physiology; Immunosuppressive Agents - pharmacology; In Situ Nick-End Labeling; Male; Mice; Mice, SCID; microglia; Neuroglia - drug effects; Neuroglia - metabolism; Neuroglia - virology; Neurons - drug effects; Neurons - metabolism; Neurons - virology; neuroprotection; Peptides - pharmacology; severe combined immunodeficient mice; Time Factors
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.20607

Virus‐infected and immune‐competent mononuclear phagocytes (MP; perivascular macrophages and microglia) drive the neuropathogenesis of human immunodeficiency virus type 1 (HIV‐1) infection. Modulation of the MP phenotype from neurodestructive to neuroprotective underlies adjunctive therapeutic strategies for human disease. We reasoned that, as Copolymer‐1 (Cop‐1) can induce neuroprotective activities in a number of neuroinflammatory and neurodegenerative disorders, it could directly modulate HIV‐1‐infected MP neurotoxic activities. We now demonstrate that, in laboratory assays, Cop‐1‐stimulated virus‐infected human monocyte‐derived macrophages (MDM) protect against neuronal injury. Severe combined immune‐deficient (SCID) mice were stereotactically injected with HIV‐1‐infected human MDM, into the basal ganglia, to induce HIV‐1 encephalitis (HIVE). Cop‐1 was administered subcutaneously for 7 days. In HIVE mice, Cop‐1 treatment led to anti‐inflammatory and neuroprotective responses. Reduced micro‐ and astrogliosis, and conserved NeuN/MAP‐2 levels were observed in virus‐affected brain regions in Cop‐1‐treated mice. These were linked to interleukin‐10 and brain‐derived neurotrophic factor expression and downregulation of inducible nitric oxide synthase. The data, taken together, demonstrate that Cop‐1 can modulate innate immunity and, as such, improve disease outcomes in an animal model of HIVE. © 2007 Wiley‐Liss, Inc.