Parvovirus glycan interactions

Huang, Li-Hsin; Halder, Sujata; Agbandje‐McKenna, Mavis

doi:10.1016/j.coviro.2014.05.007

Cited by 112 publications

(107 citation statements)

References 107 publications

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“…8). This suggests that distinct capsid regions on different AAV isolates can be responsible for the same activity (32).…”

Section: Discussionmentioning

confidence: 92%

“…What is known is that these viruses have evolved to utilize the glycans abundant on cell surfaces as essential primary attachment points for entry. In addition, available data show that the 13 characterized serotypes can be grouped into those that bind HSPG (AAV2, AAV3B, AAV6, AAV13), SIA (AAV1, AAV4, AAV5, AAV6), GAL (AAV9), and unknown (AAV7, AAV8, AAV10, and AAV11) (32).…”

Section: Discussionmentioning

confidence: 99%

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Identification and Mutagenesis of the Adeno-Associated Virus 5 Sialic Acid Binding Region

Afione

DiMattia

Halder

et al. 2015

J Virol

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As a genus, the dependoviruses use a diverse group of cell surface carbohydrates for attachment and entry. Despite the fact that a majority of adeno-associated viruses (AAVs) utilize sialic acid (SIA) for binding and transduction, this virus-carbohydrate interaction is poorly understood. Utilizing X-ray crystallography, two SIA binding regions were mapped for AAV5. The first site mapped to the depression in the center of the 3-fold axis of symmetry, while the second site was located under the ␤HI loop close to the 5-fold axis. Mutagenesis of amino acids 569 and 585 or 587 within the 3-fold depression resulted in elimination or alteration in SIA-dependent transduction, respectively. This change in SIA binding was confirmed using glycan microarrays. Mutagenesis of the second site identified a role in transduction that was SIA independent. Further studies of the mutants at the 3-fold site demonstrated a change in transduction activity and cell tropism in vivo as well as resistance to neutralization by a polyclonal antibody raised against the wild-type virus. IMPORTANCEDespite the fact that a majority of AAVs utilize sialic acid for binding and transduction, this virus-carbohydrate interaction is poorly understood. Utilizing X-ray crystallography, the sialic acid binding regions of AAV5 were identified and studied using a variety of approaches. Mutagenesis of this region resulted in elimination or alteration in sialic acid-dependent transduction in cell lines. This change in sialic acid glycan binding was confirmed using glycan arrays. Further study also demonstrated a change in transduction and activity and cell tropism in vivo as well as resistance to neutralization by antibodies raised against the wild-type virus.

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“…8). This suggests that distinct capsid regions on different AAV isolates can be responsible for the same activity (32).…”

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Identification and Mutagenesis of the Adeno-Associated Virus 5 Sialic Acid Binding Region

Afione

DiMattia

Halder

et al. 2015

J Virol

Self Cite

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“…The first step, i.e., parvoviral attachment to the host cell surface, is mediated by different glycans (10). In the brain, AAV capsid interactions with heparan sulfate (HS) have been particularly well studied.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, SA receptors have been implicated in the neurovirulence of reoviruses and polyomaviruses (8,9). Modulating SA binding affinity has also been shown to influence the pathogenicity of the neurovirulent strain of the minute virus of mice (MVM) (10).…”

mentioning

confidence: 99%

“…However, the molecular bases of this diversity in AAV transport mechanisms and CNS tropisms are not well understood. Within this framework, AAV isolates have been shown to utilize three different glycans-SA, galactose (Gal), and heparan sulfate (HS)-for cell surface attachment (10). In addition, several growth factor receptors and integrins have been identified as being essential for AAV cell entry (18).…”

mentioning

confidence: 99%

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Unique Glycan Signatures Regulate Adeno-Associated Virus Tropism in the Developing Brain

Murlidharan

Corriher

Ghashghaei

et al. 2015

J Virol

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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. IMPORTANCEViruses 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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Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno‐Associated Viral Vector rAAV9P1

Bauer

Puglisi²,

Nagl

et al. 2022

Advanced Science

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Astrocytes have crucial functions in the central nervous system (CNS) and are major players in many CNS diseases. Research on astrocyte-centered diseases requires efficient and well-characterized gene transfer vectors. Vectors derived from the Adeno-associated virus serotype 9 (AAV9) target astrocytes in the brains of rodents and nonhuman primates. A recombinant (r) synthetic peptide-displaying AAV9 variant, rAAV9P1, that efficiently and selectively transduces cultured human astrocytes, has been described previously. Here, it is shown that rAAV9P1 retains astrocyte-targeting properties upon intravenous injection in mice. Detailed analysis of putative receptors on human astrocytes shows that rAAV9P1 utilizes integrin subunits 𝜶v, 𝜷8, and either 𝜷3 or 𝜷5 as well as the AAV receptor AAVR. This receptor pattern is distinct from that of vectors derived from wildtype AAV2 or AAV9. Furthermore, a CRISPR/Cas9 genome-wide knockout screening revealed the involvement of several astrocyte-associated intracellular signaling pathways in the transduction of human astrocytes by rAAV9P1. This study delineates the unique receptor and intracellular pathway signatures utilized by rAAV9P1 for targeting human astrocytes. These results enhance the understanding of the transduction biology of synthetic rAAV vectors for astrocytes and can promote the development of advanced astrocyte-selective gene delivery vehicles for research and clinical applications.

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Parvovirus glycan interactions

Cited by 112 publications

References 107 publications

Identification and Mutagenesis of the Adeno-Associated Virus 5 Sialic Acid Binding Region

Identification and Mutagenesis of the Adeno-Associated Virus 5 Sialic Acid Binding Region

Unique Glycan Signatures Regulate Adeno-Associated Virus Tropism in the Developing Brain

Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno‐Associated Viral Vector rAAV9P1

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