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

Publication ,  Journal Article
Murlidharan, G; Corriher, T; Ghashghaei, HT; Asokan, A
Published in: J Virol
April 2015

UNLABELLED: 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.

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Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

April 2015

Volume

89

Issue

7

Start / End Page

3976 / 3987

Location

United States

Related Subject Headings

  • Virology
  • Viral Tropism
  • Transduction, Genetic
  • Sialic Acids
  • Receptors, Virus
  • Mice, Inbred BALB C
  • Dependovirus
  • Brain
  • Animals
  • 32 Biomedical and clinical sciences
 

Citation

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ICMJE
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Murlidharan, G., Corriher, T., Ghashghaei, H. T., & Asokan, A. (2015). Unique glycan signatures regulate adeno-associated virus tropism in the developing brain. J Virol, 89(7), 3976–3987. https://doi.org/10.1128/JVI.02951-14
Murlidharan, Giridhar, Travis Corriher, H Troy Ghashghaei, and Aravind Asokan. “Unique glycan signatures regulate adeno-associated virus tropism in the developing brain.J Virol 89, no. 7 (April 2015): 3976–87. https://doi.org/10.1128/JVI.02951-14.
Murlidharan G, Corriher T, Ghashghaei HT, Asokan A. Unique glycan signatures regulate adeno-associated virus tropism in the developing brain. J Virol. 2015 Apr;89(7):3976–87.
Murlidharan, Giridhar, et al. “Unique glycan signatures regulate adeno-associated virus tropism in the developing brain.J Virol, vol. 89, no. 7, Apr. 2015, pp. 3976–87. Pubmed, doi:10.1128/JVI.02951-14.
Murlidharan G, Corriher T, Ghashghaei HT, Asokan A. Unique glycan signatures regulate adeno-associated virus tropism in the developing brain. J Virol. 2015 Apr;89(7):3976–3987.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

April 2015

Volume

89

Issue

7

Start / End Page

3976 / 3987

Location

United States

Related Subject Headings

  • Virology
  • Viral Tropism
  • Transduction, Genetic
  • Sialic Acids
  • Receptors, Virus
  • Mice, Inbred BALB C
  • Dependovirus
  • Brain
  • Animals
  • 32 Biomedical and clinical sciences