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Copolymer-1 Induces Adaptive Immune Anti-inflammatory Glial and Neuroprotective Responses in a Murine Model of HIV-1 Encephalitis¹

Santhi Gorantla^*,, Jianou Liu^*,, Hannah Sneller^*,, Huanyu Dou^*,, Adelina Holguin^*,, Lynette Smith, Tsuneya Ikezu^*,, David J. Volsky^¶, Larisa Poluektova^*, and Howard E. Gendelman^2,*,,

^* Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, Internal Medicine, and Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE 68198; and ^¶ Molecular Virology Division, St. Luke’s-Roosevelt Hospital Center and Columbia University Medical Center, New York, NY 10019

Copolymer-1 (COP-1) elicits neuroprotective activities in a wide range of neurodegenerative disorders. This occurs, in part, by adaptive immune-mediated suppression of microglial inflammatory responses. Because HIV infection and immune activation of perivascular macrophages and microglia drive a metabolic encephalopathy, we reasoned that COP-1 could be developed as an adjunctive therapy for disease. To test this, we developed a novel animal model system that reflects HIV-1 encephalitis in rodents with both innate and adaptive arms of the immune system. Bone marrow-derived macrophages were infected with HIV-1/vesicular stomatitis-pseudotyped virus and stereotactically injected into the basal ganglia of syngeneic mice. HIV-1 pseudotyped with vesicular stomatitis virus envelope-infected bone marrow-derived macrophages induced significant neuroinflammation, including astrogliosis and microglial activation with subsequent neuronal damage. Importantly, COP-1 immunization reduced astro- and microgliosis while diminishing neurodegeneration. Hippocampal neurogenesis was, in part, restored. This paralleled reductions in proinflammatory cytokines, including TNF- and IL-1β, and inducible NO synthase, and increases in brain-derived neurotrophic factor. Ingress of Foxp3- and IL-4-expressing lymphocytes into brains of COP-1-immunized animals was observed. We conclude that COP-1 may warrant therapeutic consideration for HIV-1-associated cognitive impairments.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported, in part, by National Institutes of Health Grants 2 R37 NS36126, 1 P01 NS043985-01, 5 P01 MH64570-03, and P20 RR15635.

² Address correspondence and reprint requests to Dr. Howard E. Gendelman, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880. E-mail address: hegendel{at}unmc.edu

³ Abbreviations used in this paper: ART, antiretroviral therapy; AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor; BMM, bone marrow-derived macrophage; GFAP, glial fibrillary acidic protein; HIVE, HIV encephalitis; Iba-1, ionizing calcium-binding adaptor molecule 1; i.c., intracranial; iNOS, inducible NO synthase; LN, lymph node; MAP-2, microtubule-associated protein-2; MBP, myelin basic protein; NeuN, neuronal nucleus; NF, neurofilament; PD, Parkinson’s disease; PSA-NCAM, polysialylated form of neural cell adhesion molecule; VSV, vesicular stomatitis virus; COP-1, copolymer-1.

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