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J Virol. 2015 Apr;89(7):3976-87. doi: 10.1128/JVI.02951-14. Epub 2015 Jan 28.

Unique glycan signatures regulate adeno-associated virus tropism in the developing brain.

Author information

1
Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Department of Molecular Biomedical Sciences, Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
4
Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Departments of Genetics, Biochemistry & Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA aravind@med.unc.edu.

Abstract

Adeno-associated viruses (AAV) are thought to spread through the central nervous system (CNS) by exploiting cerebrospinal fluid (CSF) flux and hijacking axonal transport pathways. The role of host receptors that mediate these processes is not well understood. In the current study, we utilized AAV serotype 4 (AAV4) as a model to evaluate whether ubiquitously expressed 2,3-linked sialic acid and the developmentally regulated marker 2,8-linked polysialic acid (PSA) regulate viral transport and tropism in the neonatal brain. Modulation of the levels of SA and PSA in cell culture studies using specific neuraminidases revealed possibly opposing roles of the two glycans in AAV4 transduction. Interestingly, upon intracranial injection into lateral ventricles of the neonatal mouse brain, a low-affinity AAV4 mutant (AAV4.18) displayed a striking shift in cellular tropism from 2,3-linked SA(+) ependymal lining to 2,8-linked PSA(+) migrating progenitors in the rostral migratory stream and olfactory bulb. In addition, this gain-of-function phenotype correlated with robust CNS spread of AAV4.18 through paravascular transport pathways. Consistent with these observations, altering glycan dynamics within the brain by coadministering SA- and PSA-specific neuraminidases resulted in striking changes to the cellular tropisms and transduction efficiencies of both parental and mutant vectors. We postulate that glycan signatures associated with host development can be exploited to redirect novel AAV vectors to specific cell types in the brain.

IMPORTANCE:

Viruses invade the CNS through various mechanisms. In the current study, we utilized AAV as a model to study the dynamics of virus-carbohydrate interactions in the developing brain and their impact on viral tropism. Our findings suggest that carbohydrate content can be exploited to regulate viral transport and tropism in the brain.

PMID:
25631075
PMCID:
PMC4403422
DOI:
10.1128/JVI.02951-14
[Indexed for MEDLINE]
Free PMC Article

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