PMID- 29343568
OWN - NLM
STAT- MEDLINE
DCOM- 20180417
LR  - 20190319
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 7
DP  - 2018 Apr 1
TI  - An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV 
      Receptor.
LID - 10.1128/JVI.02213-17 [doi]
LID - e02213-17
AB  - Determinants and mechanisms of cell attachment and entry steer adeno-associated 
      virus (AAV) in its utility as a gene therapy vector. Thus far, a systematic 
      assessment of how diverse AAV serotypes engage their proteinaceous receptor AAVR 
      (KIAA0319L) to establish transduction has been lacking, despite potential 
      implications for cell and tissue tropism. Here, a large set of human and simian 
      AAVs as well as in silico-reconstructed ancestral AAV capsids were interrogated 
      for AAVR usage. We identified a distinct AAV capsid lineage comprised of AAV4 and 
      AAVrh32.33 that can bind and transduce cells in the absence of AAVR, independent 
      of the multiplicity of infection. Virus overlay assays and rescue experiments in 
      nonpermissive cells demonstrate that these AAVs are unable to bind to or use the 
      AAVR protein for entry. Further evidence for a distinct entry pathway was 
      observed in vivo, as AAVR knockout mice were equally as permissive to 
      transduction by AAVrh32.33 as wild-type mice upon systemic injection. We 
      interestingly observe that some AAV capsids undergo a low level of transduction 
      in the absence of AAVR, both in vitro and in vivo, suggesting that some capsids 
      may have a multimodal entry pathway. In aggregate, our results demonstrate that 
      AAVR usage is conserved among all primate AAVs except for those of the AAV4 
      lineage, and a non-AAVR pathway may be available to other serotypes. This work 
      furthers our understanding of the entry of AAV, a vector system of broad utility 
      in gene therapy.IMPORTANCE Adeno-associated virus (AAV) is a nonpathogenic virus 
      that is used as a vehicle for gene delivery. Here, we have identified several 
      situations in which transduction is retained in both cell lines and a mouse model 
      in the absence of a previously defined entry receptor, AAVR. Defining the 
      molecular determinants of the infectious pathway of this highly relevant viral 
      vector system can help refine future applications and therapies with this vector.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Dudek, Amanda M
AU  - Dudek AM
AD  - Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts 
      Eye and Ear Infirmary, Boston, Massachusetts, USA.
AD  - Harvard Ph.D. Program in Virology, Division of Medical Sciences, Harvard 
      University, Boston, Massachusetts, USA.
AD  - Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Pillay, Sirika
AU  - Pillay S
AD  - Department of Microbiology and Immunology, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Puschnik, Andreas S
AU  - Puschnik AS
AD  - Department of Microbiology and Immunology, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Nagamine, Claude M
AU  - Nagamine CM
AD  - Department of Comparative Medicine, Stanford University School of Medicine, 
      Stanford, California, USA.
FAU - Cheng, Fang
AU  - Cheng F
AD  - Department of Microbiology, Molecular Genetics and Immunology, University of 
      Kansas Medical Center, Kansas City, Kansas, USA.
FAU - Qiu, Jianming
AU  - Qiu J
AD  - Department of Microbiology, Molecular Genetics and Immunology, University of 
      Kansas Medical Center, Kansas City, Kansas, USA.
FAU - Carette, Jan E
AU  - Carette JE
AD  - Department of Microbiology and Immunology, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Vandenberghe, Luk H
AU  - Vandenberghe LH
AUID- ORCID: 0000-0002-3508-4924
AD  - Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts 
      Eye and Ear Infirmary, Boston, Massachusetts, USA 
      Luk_Vandenberghe@MEEI.harvard.edu.
AD  - Harvard Ph.D. Program in Virology, Division of Medical Sciences, Harvard 
      University, Boston, Massachusetts, USA.
AD  - Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, 
      Boston, Massachusetts, USA.
AD  - The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
LA  - eng
GR  - DP2 AI104557/AI/NIAID NIH HHS/United States
GR  - P30 EY003790/EY/NEI NIH HHS/United States
GR  - R21 AI112803/AI/NIAID NIH HHS/United States
GR  - U19 AI109662/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180314
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (KIAA0319L protein, mouse)
RN  - 0 (Receptors, Cell Surface)
SB  - IM
MH  - Animals
MH  - Capsid/*metabolism
MH  - Cell Line
MH  - *Dependovirus/genetics/metabolism
MH  - *Genetic Vectors
MH  - Mice
MH  - Mice, Knockout
MH  - Receptors, Cell Surface/genetics/metabolism
MH  - *Transduction, Genetic
MH  - *Virus Internalization
PMC - PMC5972900
OTO - NOTNLM
OT  - AAV
OT  - adeno-associated virus
OT  - attachment
OT  - gene therapy
OT  - vector
OT  - viral entry
OT  - viral gene transfer
OT  - virus
OT  - virus receptor
EDAT- 2018/01/19 06:00
MHDA- 2018/04/18 06:00
PMCR- 2018/09/14
CRDT- 2018/01/19 06:00
PHST- 2018/01/02 00:00 [received]
PHST- 2018/01/03 00:00 [accepted]
PHST- 2018/01/19 06:00 [pubmed]
PHST- 2018/04/18 06:00 [medline]
PHST- 2018/01/19 06:00 [entrez]
PHST- 2018/09/14 00:00 [pmc-release]
AID - JVI.02213-17 [pii]
AID - 02213-17 [pii]
AID - 10.1128/JVI.02213-17 [doi]
PST - epublish
SO  - J Virol. 2018 Mar 14;92(7):e02213-17. doi: 10.1128/JVI.02213-17. Print 2018 Apr 
      1.