title: AAV9-mediated expression of a non-self protein in nonhuman primate central nervous system triggers widespread neuroinflammation driven by antigen-presenting cell transduction.
abstract: Many studies have demonstrated that adeno-associated virus serotype 9 (AAV9) transduces astrocytes and neurons when infused into rat or nonhuman primate (NHP) brain. We previously showed in rats that transduction of antigen-presenting cells (APC) by AAV9 encoding a foreign protein triggered a full neurotoxic immune response. Accordingly, we asked whether this phenomenon occurred in NHP. We performed parenchymal or intrathecal infusion of AAV9 encoding green fluorescent protein (GFP), a non-self protein derived from jellyfish, or human aromatic L-amino acid decarboxylase (hAADC), a self-protein, in separate NHP. Animals receiving AAV9-GFP into cisterna magna (CM) became ataxic, indicating cerebellar pathology, whereas AAV9-hAADC animals remained healthy. In transduced regions, AAV9-GFP elicited inflammation associated with early activation of astrocytic and microglial cells, along with upregulation of major histocompatibility complex class II (MHC-II) in glia. In addition, we found Purkinje neurons lacking calbindin after AAV9-GFP but not after AAV9-hAADC delivery. Our results demonstrate that AAV9-mediated expression of a foreign-protein, but not self-recognized protein, triggers complete immune responses in NHP regardless of the route of administration. Our results warrant caution when contemplating use of serotypes that can transduce APC if the transgene is not syngeneic with the host. This finding has the potential to complicate preclinical toxicology studies in which such vectors encoding human cDNA's are tested in animals.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: Lluis
authors.initials: L
authors.lastname: Samaranch
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: Waldy San
authors.initials: WS
authors.lastname: Sebastian
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kells
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA; Current address: Department of Neurological Surgery, Laboratory for CNS Repair, Brain and Spinal Cord Injury Center, University of California San Francisco, San Francisco, California, USA.
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Salegio
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Heller
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Bringas
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Pivirotto
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: DeArmond
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. Electronic address: Krystof.Bankiewicz@ucsf.edu.
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins