Copolymer-1 induces adaptive immune anti-inflammatory glial and neuroprotective responses in a murine model of HIV-1 encephalitis.
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-alpha and IL-1beta, 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.
Gorantla
Santhi
S
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Liu
Jianou
J
Sneller
Hannah
H
Dou
Huanyu
H
Holguin
Adelina
A
Smith
Lynette
L
Ikezu
Tsuneya
T
Volsky
David J
DJ
Poluektova
Larisa
L
Gendelman
Howard E
HE
D000220:Adaptation, Biological / Q000187:drug effects / Q000276:immunology; D000818:Animals; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D000068717:Glatiramer Acetate; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology; D010455:Peptides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology
D018696:Neuroprotective Agents; D010455:Peptides; D000068717:Glatiramer Acetate