PMID- 24419081 OWN - NLM STAT- MEDLINE DCOM- 20141126 LR - 20211021 IS - 1525-0024 (Electronic) IS - 1525-0016 (Print) IS - 1525-0016 (Linking) VI - 22 IP - 2 DP - 2014 Feb TI - AAV9-mediated expression of a non-self protein in nonhuman primate central nervous system triggers widespread neuroinflammation driven by antigen-presenting cell transduction. PG - 329-337 LID - S1525-0016(16)31154-6 [pii] LID - 10.1038/mt.2013.266 [doi] AB - 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. FAU - Samaranch, Lluis AU - Samaranch L AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Sebastian, Waldy San AU - Sebastian WS AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Kells, Adrian P AU - Kells AP AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Salegio, Ernesto A AU - Salegio EA AD - 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. FAU - Heller, Gregory AU - Heller G AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Bringas, John R AU - Bringas JR AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Pivirotto, Philip AU - Pivirotto P AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - DeArmond, Stephen AU - DeArmond S AD - Department of Pathology and Laboratory Medicine, University of California San Francisco, San Francisco, California, USA. FAU - Forsayeth, John AU - Forsayeth J AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. FAU - Bankiewicz, Krystof S AU - Bankiewicz KS AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA. Electronic address: Krystof.Bankiewicz@ucsf.edu. LA - eng GR - R01 NS073940/NS/NINDS NIH HHS/United States GR - R01NS073940-01/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131121 PL - United States TA - Mol Ther JT - Molecular therapy : the journal of the American Society of Gene Therapy JID - 100890581 RN - 147336-22-9 (Green Fluorescent Proteins) SB - IM CIN - Mol Ther. 2014 Feb;22(2):246-7. PMID: 24487564 MH - Animals MH - Antigen-Presenting Cells/*immunology/*metabolism MH - Central Nervous System/*immunology/*metabolism/pathology MH - Corpus Striatum/immunology/metabolism/pathology MH - *Dependovirus/genetics/immunology MH - Gene Expression MH - Genes, Reporter MH - *Genetic Vectors/administration & dosage/genetics/immunology MH - Green Fluorescent Proteins/genetics MH - Humans MH - Inflammation/*genetics/*immunology/pathology MH - Neurons/metabolism/pathology MH - Rats MH - Transduction, Genetic MH - Transgenes PMC - PMC3918916 EDAT- 2014/01/15 06:00 MHDA- 2014/12/15 06:00 PMCR- 2015/02/01 CRDT- 2014/01/15 06:00 PHST- 2013/05/14 00:00 [received] PHST- 2013/11/15 00:00 [accepted] PHST- 2014/01/15 06:00 [entrez] PHST- 2014/01/15 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2015/02/01 00:00 [pmc-release] AID - S1525-0016(16)31154-6 [pii] AID - 10.1038/mt.2013.266 [doi] PST - ppublish SO - Mol Ther. 2014 Feb;22(2):329-337. doi: 10.1038/mt.2013.266. Epub 2013 Nov 21.