PMID- 22787229
OWN - NLM
STAT- MEDLINE
DCOM- 20121129
LR  - 20211021
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 86
IP  - 19
DP  - 2012 Oct
TI  - Glycan binding avidity determines the systemic fate of adeno-associated virus 
      type 9.
PG  - 10408-17
LID - 10.1128/JVI.01155-12 [doi]
AB  - Glycans are key determinants of host range and transmissibility in several 
      pathogens. In the case of adeno-associated viruses (AAV), different carbohydrates 
      serve as cellular receptors in vitro; however, their contributions in vivo are 
      less clear. A particularly interesting example is adeno-associated virus serotype 
      9 (AAV9), which displays systemic tropism in mice despite low endogenous levels 
      of its primary receptor (galactose) in murine tissues. To understand this 
      further, we studied the effect of modulating glycan binding avidity on the 
      systemic fate of AAV9 in mice. Intravenous administration of recombinant 
      sialidase increased tissue levels of terminally galactosylated glycans in several 
      murine tissues. These conditions altered the systemic tropism of AAV9 into a 
      hepatotropic phenotype, characterized by markedly increased sequestration within 
      the liver sinusoidal endothelium and Kupffer cells. In contrast, an AAV9 mutant 
      with decreased glycan binding avidity displayed a liver-detargeted phenotype. 
      Altering glycan binding avidity also profoundly affected AAV9 persistence in 
      blood circulation. Our results support the notion that high glycan receptor 
      binding avidity appears to impart increased liver tropism, while decreased 
      avidity favors systemic spread of AAV vectors. These findings may not only help 
      predict species-specific differences in tropism for AAV9 on the basis of tissue 
      glycosylation profiles, but also provide a general approach to tailor AAV vectors 
      for systemic or hepatic gene transfer by reengineering capsid-glycan 
      interactions.
FAU - Shen, Shen
AU  - Shen S
AD  - Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, 
      North Carolina, USA.
FAU - Bryant, Kelli D
AU  - Bryant KD
FAU - Sun, Junjiang
AU  - Sun J
FAU - Brown, Sarah M
AU  - Brown SM
FAU - Troupes, Andrew
AU  - Troupes A
FAU - Pulicherla, Nagesh
AU  - Pulicherla N
FAU - Asokan, Aravind
AU  - Asokan A
LA  - eng
GR  - P30 CA016086/CA/NCI NIH HHS/United States
GR  - R01 HL089221/HL/NHLBI NIH HHS/United States
GR  - HL089221-01A1/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120711
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Polysaccharides)
RN  - X2RN3Q8DNE (Galactose)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Capsid/chemistry
MH  - Cell Membrane/metabolism
MH  - Cricetinae
MH  - Dependovirus/*metabolism
MH  - Endothelial Cells/cytology
MH  - Erythrina/metabolism
MH  - Female
MH  - Galactose/chemistry
MH  - HEK293 Cells
MH  - Humans
MH  - Kupffer Cells/cytology
MH  - Liver/cytology
MH  - Maackia/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Polysaccharides/*chemistry
MH  - Protein Binding
MH  - Rats
MH  - Vibrio cholerae/metabolism
PMC - PMC3457279
EDAT- 2012/07/13 06:00
MHDA- 2012/12/10 06:00
PMCR- 2013/04/01
CRDT- 2012/07/13 06:00
PHST- 2012/07/13 06:00 [entrez]
PHST- 2012/07/13 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - JVI.01155-12 [pii]
AID - 01155-12 [pii]
AID - 10.1128/JVI.01155-12 [doi]
PST - ppublish
SO  - J Virol. 2012 Oct;86(19):10408-17. doi: 10.1128/JVI.01155-12. Epub 2012 Jul 11.