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

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Abstract
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.
Funding Information
  • National Institute of Health (1T32 NS07488, 2R37 NS36136, PO1 NS43985, PO1 MH64570, R01 MH79886, P20RR15635)