Terminal N-Linked Galactose Is the Primary Receptor for Adeno-associated Virus 9

Shen, Shen; Bryant, Kelli D.; Brown, Sarah M.; Randell, Scott H.; Asokan, Aravind

doi:10.1074/jbc.m110.210922

Cited by 234 publications

(216 citation statements)

References 47 publications

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“…28 More recently, N-terminal linked galactose has been characterised as a major receptor for AAV9. 29 AAV serotypes 8 and 9 have been shown to efficiently transduce cells in the neonatal mouse 7 and adult non-human primate brains. 30 These data, taken together with our findings, suggest that the receptor required for AAV2/8 and 2/9 transduction is present from gestation through to adulthood in mice.…”

Section: Discussionmentioning

confidence: 99%

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

et al. 2011

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The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.

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Section: Discussionmentioning

confidence: 99%

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

et al. 2011

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“…AAV entry is initiated by cell surface receptor recognition, and for seven of the nine representative AAV serotypes, glycans have been reported to serve as primary receptors. AAV1 binds both ␣2-3 and ␣2-6 N-linked sialic acid (SIA) (77-79), AAV2 and AAV3B bind to heparan sulfate (HS) (80,81), AAV4 binds ␣2-3 O-linked sialic acids, AAV5 binds ␣2-3 N-linked SIA (82-84), AAV6 binds both HS and SIA (78,85), and AAV9 binds to galactose (86)(87)(88). The glycan receptor (if any) utilized by AAV7 and AAV9 is yet to be determined.…”

Section: Fig 2 Aav Capsid Surfaces (A Cmentioning

confidence: 99%

Structural Insights into Adeno-Associated Virus Serotype 5

Govindasamy

DiMattia

Gurda

et al. 2013

J Virol

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The adeno-associated viruses (AAVs) display differential cell binding, transduction, and antigenic characteristics specified by their capsid viral protein (VP) composition. Toward structure-function annotation, the crystal structure of AAV5, one of the most sequence diverse AAV serotypes, was determined to 3.45-Å resolution. The AAV5 VP and capsid conserve topological features previously described for other AAVs but uniquely differ in the surface-exposed HI loop between ␤H and ␤I of the core ␤-barrel motif and have pronounced conformational differences in two of the AAV surface variable regions (VRs), VR-IV and VR-VII. The HI loop is structurally conserved in other AAVs despite amino acid differences but is smaller in AAV5 due to an amino acid deletion. This HI loop is adjacent to VR-VII, which is largest in AAV5. The VR-IV, which forms the larger outermost finger-like loop contributing to the protrusions surrounding the icosahedral 3-fold axes of the AAVs, is shorter in AAV5, creating a smoother capsid surface topology. The HI loop plays a role in AAV capsid assembly and genome packaging, and VR-IV and VR-VII are associated with transduction and antigenic differences, respectively, between the AAVs. A comparison of interior capsid surface charge and volume of AAV5 to AAV2 and AAV4 showed a higher propensity of acidic residues but similar volumes, consistent with comparable DNA packaging capacities. This structure provided a three-dimensional (3D) template for functional annotation of the AAV5 capsid with respect to regions that confer assembly efficiency, dictate cellular transduction phenotypes, and control antigenicity. R ecombinant adeno-associated viruses (rAAVs) are promising viral vectors for gene delivery applications (1, 2). These viruses belong to the single-stranded DNA (ssDNA)-packaging Parvoviridae and genus Dependovirus. Hundreds of AAV genotypes have been sequenced from several mammalian species, and to date 12 serotypes (AAV1 to AAV12) have been defined for the human and nonhuman primate isolates (3-15). The 12 serotypes are classified into eight genetic groups, clades A to F and clonal isolates AAV4 and AAV5, based on antigenic reactivity and sequence similarity (15). The groups are represented by AAV1 to AAV9, with AAV1 and AAV6 belonging to the same clade A because of their high sequence similarity and antigenic cross-reactivity. The representative members share ϳ55 to 99% sequence identity, with AAV4 and AAV5 being the most divergent from each other and from the other members.The linear ssDNA AAV genome, ϳ4.7 kb in length, contains two genes: cap, which encodes the capsid viral proteins (VPs; VP1, ϳ87 kDa; VP2, ϳ73 kDa; VP3, ϳ62 kDa) and rep, which encodes the replication proteins necessary for genome replication and genome packaging. Inverted terminal repeats (ITRs) at the end of the AAV genome, 145 bp in length, are the only essential active sequence required to function as (i) the origin for DNA replication, (ii) the packaging signal, and (iii) integration sites (16)(17)(18)(19). Recombina...

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“…The efficient internalization of AAV vectors into different cell types is mediated by the binding of virions to ubiquitously expressed cell surface receptors (7,8); tropism is further expanded by the availability of over a dozen different viral serotypes (9)(10)(11)(12). Restriction of permissivity, however, mainly occurs at the postentry level, where multiple barriers constrain vector transduction.…”

mentioning

confidence: 99%

Genome-wide RNAi screening identifies host restriction factors critical for in vivo AAV transduction

Mano

Ippodrino

Zentilin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Viral vectors based on the adeno-associated virus (AAV) hold great promise for in vivo gene transfer; several unknowns, however, still limit the vectors' broader and more efficient application. Here, we report the results of a high-throughput, whole-genome siRNA screening aimed at identifying cellular factors regulating AAV transduction. We identified 1,483 genes affecting vector efficiency more than 4-fold and up to 50-fold, either negatively or positively. Most of these factors have not previously been associated to AAV infection. The most effective siRNAs were independent from the virus serotype or analyzed cell type and were equally evident for single-stranded and self-complementary AAV vectors. A common characteristic of the most effective siRNAs was the induction of cellular DNA damage and activation of a cell cycle checkpoint. This information can be exploited for the development of more efficient AAV-based gene delivery procedures. Administration of the most effective siRNAs identified by the screening to the liver significantly improved in vivo AAV transduction efficiency.adeno-associated virus | DNA-damage response | high-throughput screening | self-complementary vectors | RNA interference V iral vectors based on the adeno-associated virus (AAV) have received incremental attention over the past two decades as effective tools for in vivo gene transfer. The vectors' intrinsic structural simplicity, lack of pathogenicity, low immunogenicity, and ability to mediate long-term, episomal expression in nondividing cells in vitro and, most notably, postmitotic organs in vivo are desirable characteristics for several gene therapy applications (reviewed in ref. 1). Indeed, to date, over 90 clinical trials using these vectors have been carried out (www.abedia.com/wiley/index. html); the first commercial gene therapy product (Glybera) is an AAV1 vector for the treatment of familial lipoprotein lipase deficiency (2).Despite these achievements, AAV vectors still display an undeniable number of limitations in terms of restricted cellular permissivity and efficacy of transgene expression. Efficient transduction in vivo is essentially limited to postmitotic cells [in particular, cardiomyocytes, neurons, retinal cells, and skeletal muscle fibers (1)] and requires infection at a relatively high multiplicity of infection; in addition, vector-driven gene expression is achieved only after a relatively long lag period (3). These characteristics are still incompletely understood in molecular terms but certainly reside within the intrinsic biological properties of target cells. This finding is also highlighted by the peculiar biology of wild-type AAV, which, for the completion of its biological cycle, requires cellular coinfection by adenovirus or other viruses that modify the cellular environment of the target cells, rendering them permissive for viral replication (4-6).The efficient internalization of AAV vectors into different cell types is mediated by the binding of virions to ubiquitously expressed cell surface receptors (...

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Terminal N-Linked Galactose Is the Primary Receptor for Adeno-associated Virus 9

Cited by 234 publications

References 47 publications

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

Structural Insights into Adeno-Associated Virus Serotype 5

Genome-wide RNAi screening identifies host restriction factors critical for in vivo AAV transduction

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