Adeno-associated virus 2 bound to its cellular receptor AAVR

Zhang, Ran; Cao, Lin; Cui, Mengtian; Sun, Zhenli; Hu, M.H.; Zhang, Rouxuan; Stuart, William D.; Zhao, Xiaochu; Yang, Zheyuan; Li, Xueming; Sun, Yuna; Li, Shentao; Ding, Wei; Lou, Zhiyong; Rao, Zihe

doi:10.1038/s41564-018-0356-7

Cited by 87 publications

(155 citation statements)

References 33 publications

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“…The most commonly manipulated position within the AAV capsid is the surface-exposed loop containing amino acid (AA) 588 because it is the site of heparan sulfate binding in AAV2 31 and is amenable to peptide display 32,33 . The only known receptors for AAV9 are N-linked terminal galactose 34 and the AAV receptor (AAVR) 35,36 , but the possibility of co-receptors is still unexplored. Binding interactions with cell-surface receptors occur near the 3-fold axis of symmetry of the AAV9 viral capsid (Fig.…”

Section: Engineering Aav Capsids At the 3-fold Point Of Symmetrymentioning

confidence: 99%

Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

Flytzanis

Goeden

Goertsen

et al. 2020

Preprint

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Genetic intervention is increasingly explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies relies upon expressing a transgene in affected cells while minimizing off-target expression. To achieve organ/cell-type specific targeting after intravenous delivery of viral vectors, we employed a Cre-transgenic-based screening platform for fast and efficient capsid selection, paired with sequential engineering of multiple surface-exposed loops. We identified capsid variants that are enriched in the brain and detargeted from the liver in mice. The improved enrichment in the brain extends to nonhuman primates, enabling robust, non-invasive gene delivery to the marmoset brain following IV administration. Importantly, the capsids identified display non-overlapping cell-type tropisms within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood-brain barrier with cell-type specificity in rodents and nonhuman primates enables new avenues for basic research and potential therapeutic interventions unattainable with naturally occurring serotypes. Affiliations

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Section: Engineering Aav Capsids At the 3-fold Point Of Symmetrymentioning

confidence: 99%

Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

Flytzanis

Goeden

Goertsen

et al. 2020

Preprint

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“…Our understanding of AAV capsid interactions with serum factors is still evolving, wherein structural information and the impact of serum protein glycosylation on such interactions remain to be elucidated. However, it is worth highlighting the structural footprint for AAV2 capsid-AAVR interactions that was recently reported (28). Interestingly, residues within the VR1 region (S262, Q263, G265, A266, S267, N268, and H271) in one of the AAV2 VP3 monomer subunits play a significant role in determining capsid interactions with AAVR.…”

Section: Discussionmentioning

confidence: 82%

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

Albright

Simon

Pillai

et al. 2019

J Virol

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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.

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“…The r.m.s.d.s for VR-IV (amino acids 449-477), VR-V (amino acids 493-512) and VR-VIII (amino acids 578-600) are 0.422, 0.326 and 0.302 Å , respectively. In other serotypes, these areas are known to be hotspots for binding cellular protein receptors and glycan receptors, as well as neutralizing antibodies (Zhang et al, 2019;Meyer et al, 2019;Bell et al, 2012;O'Donnell et al, 2009;Giles et al, 2018;Huang et al, 2016;Tseng & Agbandje-McKenna, 2014). Although VR-VIII has the lowest amino-acid identity of any region between AAVhu.37 and AAV8 (70%), the main chain is scarcely perturbed.…”

Section: Comparison To Known Serotypesmentioning

confidence: 99%

Structure of the AAVhu.37 capsid by cryoelectron microscopy

Kaelber

Yost

Webber

et al. 2020

Acta Crystallogr F Struct Biol Commun

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Adeno‐associated viruses (AAVs) are used as in vivo gene‐delivery vectors in gene‐therapy products and have been heavily investigated for numerous indications. Over 100 naturally occurring AAV serotypes and variants have been isolated from primate samples. Many reports have described unique properties of these variants (for instance, differences in potency, target cell or evasion of the immune response), despite high amino‐acid sequence conservation. AAVhu.37 is of interest for clinical applications owing to its proficient transduction of the liver and central nervous system. The sequence identity of the AAVhu.37 VP1 to the well characterized AAVrh.10 serotype, for which no structure is available, is greater than 98%. Here, the structure of the AAVhu.37 capsid at 2.56 Å resolution obtained via single‐particle cryo‐electron microscopy is presented.

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Adeno-associated virus 2 bound to its cellular receptor AAVR

Cited by 87 publications

References 33 publications

Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

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

Structure of the AAVhu.37 capsid by cryoelectron microscopy

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