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

Santhi Gorantla, Jianuo Liu, Tong Wang, Adelina Holguin, Hannah M. Sneller, Huanyu Dou, Jonathan Kipnis, Larisa Y Poluektova, Howard Eliot Gendelman

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalGlia
Volume56
Issue number2
DOIs
StatePublished - Jan 15 2008

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Keywords

  • Anti-inflammatory
  • Copolymer-1
  • HIV encephalitis
  • Human immunodeficiency virus
  • Microglia
  • Neuroprotection
  • Severe combined immunodeficient mice

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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