Skip to main content

Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses.

Publication ,  Journal Article
Albright, BH; Simon, KE; Pillai, M; Devlin, GW; Asokan, A
Published in: J Virol
June 1, 2019

Central nervous system (CNS) transduction by systemically administered recombinant adeno-associated viral (AAV) vectors requires crossing the blood-brain barrier (BBB). We recently mapped a structural footprint on the AAVrh.10 capsid, which, when grafted onto the AAV1 capsid (AAV1RX), enables viral transport across the BBB; however, the underlying mechanisms remain unknown. Here, we establish through structural modeling that this footprint overlaps in part the sialic acid (SIA) footprint on AAV1. We hypothesized that altered SIA-capsid interactions may influence the ability of AAV1RX to transduce the CNS. Using AAV1 variants with altered SIA footprints, we map functional attributes of these capsids to their relative SIA dependence. Specifically, capsids with ablated SIA binding can penetrate and transduce the CNS with low to moderate efficiency. In contrast, AAV1 shows strong SIA dependency and does not transduce the CNS after systemic administration and, instead, transduces the vasculature and the liver. The AAV1RX variant, which shows an intermediate SIA binding phenotype, effectively enters the brain parenchyma and transduces neurons at levels comparable to the level of AAVrh.10. In corollary, the reciprocal swap of the AAV1RX footprint onto AAVrh.10 (AAVRX1) attenuated CNS transduction relative to that of AAVrh.10. We conclude that the composition of residues within the capsid variable region 1 (VR1) of AAV1 and AAVrh.10 profoundly influences tropism, with altered SIA interactions playing a partial role in this phenotype. Further, we postulate a Goldilocks model, wherein optimal glycan interactions can influence the CNS transduction profile of AAV capsids.IMPORTANCE Understanding how viruses cross the blood-brain barrier can provide insight into new approaches to block infection by pathogens or the ability to exploit these pathways for designing new recombinant viral vectors for gene therapy. In this regard, modulation of virus-carbohydrate interactions by mutating the virion shell can influence the ability of recombinant viruses to cross the vascular barrier, enter the brain, and enable efficient gene transfer to neurons.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

June 1, 2019

Volume

93

Issue

11

Location

United States

Related Subject Headings

  • Virology
  • Virion
  • Tropism
  • Transduction, Genetic
  • Protein Binding
  • N-Acetylneuraminic Acid
  • Humans
  • HEK293 Cells
  • Genetic Vectors
  • Genetic Therapy
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Albright, B. H., Simon, K. E., Pillai, M., Devlin, G. W., & Asokan, A. (2019). Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses. J Virol, 93(11). https://doi.org/10.1128/JVI.00332-19
Albright, Blake H., Katherine E. Simon, Minakshi Pillai, Garth W. Devlin, and Aravind Asokan. “Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses.J Virol 93, no. 11 (June 1, 2019). https://doi.org/10.1128/JVI.00332-19.
Albright, Blake H., et al. “Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses.J Virol, vol. 93, no. 11, June 2019. Pubmed, doi:10.1128/JVI.00332-19.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

June 1, 2019

Volume

93

Issue

11

Location

United States

Related Subject Headings

  • Virology
  • Virion
  • Tropism
  • Transduction, Genetic
  • Protein Binding
  • N-Acetylneuraminic Acid
  • Humans
  • HEK293 Cells
  • Genetic Vectors
  • Genetic Therapy