Modulation of innate immunity by copolymer-1 leads to neuroprotection in murine HIV-1 encephalitis.
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.
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
Santhi
S
Gorantla
Jianuo
J
Liu
Tong
T
Wang
Adelina
A
Holguin
Hannah M
HM
Sneller
Huanyu
H
Dou
Jonathan
J
Kipnis
Larisa
L
Poluektova
Howard E
HE
Gendelman
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018792:Encephalitis, Viral / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D000068717:Glatiramer Acetate; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D010455:Peptides / Q000494:pharmacology*; D013997:Time Factors
D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D010455:Peptides; D000068717:Glatiramer Acetate