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TitleReceptor Switching in Newly Evolved Adeno-associated Viruses.
Journal, issue, pagesJ Virol, Vol. 95, Issue 19, Page e0058721, Year 2021
Publish dateSep 9, 2021
AuthorsL Patrick Havlik / Anshuman Das / Mario Mietzsch / Daniel K Oh / Jonathan Ark / Robert McKenna / Mavis Agbandje-McKenna / Aravind Asokan /
PubMed AbstractAdeno-associated viruses utilize different glycans and the AAV receptor (AAVR) for cellular attachment and entry. Directed evolution has yielded new AAV variants; however, structure-function ...Adeno-associated viruses utilize different glycans and the AAV receptor (AAVR) for cellular attachment and entry. Directed evolution has yielded new AAV variants; however, structure-function correlates underlying their improved transduction are generally overlooked. Here, we report that infectious cycling of structurally diverse AAV surface loop libraries yields functionally distinct variants. Newly evolved variants show enhanced cellular binding, uptake, and transduction, but through distinct mechanisms. Using glycan-based and genome-wide CRISPR knockout screens, we discover that one AAV variant acquires the ability to recognize sulfated glycosaminoglycans, while another displays receptor switching from AAVR to integrin β1 (ITGB1). A previously evolved variant, AAVhum.8, preferentially utilizes the ITGB1 receptor over AAVR. Visualization of the AAVhum.8 capsid by cryoelectron microscopy at 2.49-Å resolution localizes the newly acquired integrin recognition motif adjacent to the AAVR footprint. These observations underscore the new finding that distinct AAV surface epitopes can be evolved to exploit different cellular receptors for enhanced transduction. Understanding how viruses interact with host cells through cell surface receptors is central to discovery and development of antiviral therapeutics, vaccines, and gene transfer vectors. Here, we demonstrate that distinct epitopes on the surface of adeno-associated viruses can be evolved by infectious cycling to recognize different cell surface carbohydrates and glycoprotein receptors and solve the three-dimensional structure of one such newly evolved AAV capsid, which provides a roadmap for designing viruses with improved attributes for gene therapy applications.
External linksJ Virol / PubMed:34232726 / PubMed Central
MethodsEM (single particle)
Resolution2.49 Å
Structure data

23516

7ltm

EMDB-23516, PDB-7ltm:
Hum8 capsid
Method: EM (single particle) / Resolution: 2.49 Å

Chemicals

ChemComp-DA:
2'-DEOXYADENOSINE-5'-MONOPHOSPHATE / dAMP*YM / Deoxyadenosine monophosphate

Source
  • adeno-associated virus - 8
KeywordsVIRUS / Icosahedral Capsid / AAV8 / Hum8 / capsid engineering / Adeno-associated virus / Parvovirus / Gene Therapy

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