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• W3016597445 abstract "Adeno-associated virus (AAV) is a small human single-stranded parvovirus. Interest centers upon the use of recombinant forms (rAAV) as delivery vectors in gene therapy, the first of which have been gaining FDA approval. An understanding of the molecular interactions on cell entry is a foundation for the design of vectors with greater tissue specificity. In 2016, we revisited the identity of cell receptors, with a genome-wide deep-sequencing of haploid human cells selected from gene-trap mutant library. We enriched the population of AAV-resistant cells, thorough fluorescence activated cell-sorting, using an rAAV encoding mCherry, allowing us to identify host-factors needed for AAV transduction. Foremost was an uncharacterized membrane protein, AAVR, that is needed for trafficking from the cell surface to the perinuclear trans Golgi network. After identifying the extracellular domains of AAVR that interact with AAV, we have expressed soluble domain fragments and have recently obtained structures of complexes at about 2.5 Å by cryo-electron microscopy (EM). The highest resolution structures have come from complexes with just the two N-terminal PKD domains, allowing us to minimize conflicts between receptors bound at adjacent sites on the virus surface related by symmetry. However, the high resolution structures are fully consistent with cryo-electron tomography, where we see (at about 3nm resolution) not only the domains bound directly, but those linked by flexible hinges as they adopt several configurations. Thus, this is an illustration of a holistic understanding of a flexible complex coming from different constructs amenable to studies at different resolutions. AAV serotype 2 (AAV-2) interacts primarily with AAVR’s polycystic kidney disease (PKD) domain 2 at a relatively conserved part of the viral surface which is also targeted by some of AAV’s most neutralizing monoclonal antibodies. Intriguingly, binding studies, mutation, and now EM structure, show that AAV-5 interacts more exclusively with PKD domain 1 at a non-overlapping site on the virus. In addition to providing a lead in understanding the differential cell specificities of different AAVs, these unexpected results pose interesting questions regarding the evolution of virus-host interactions, specifically in the emergence of distinct sets of molecular interactions among related viruses that still target the same receptor. Support or Funding Information Funded by R35 GM122564 (MSC)." @default.
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• W3016597445 date "2020-04-01" @default.
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• W3016597445 title "Diverse Interactions of Adeno‐Associated Viruses (AAV) with Cell Receptor, AAVR – Binding Studies Supported by Cryo ‐Electron Microscopy at 2.5 Å Resolution, Relevant to Gene Therapy" @default.
• W3016597445 doi "https://doi.org/10.1096/fasebj.2020.34.s1.06849" @default.
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