Cell-surface glycans recognized by the AAV capsid

Cell-surface glycans serve as the primary attachment factors and receptors for various serotypes of the Adeno-associated virus (AAV), a leading platform for gene therapy delivery. These glycans, which include heparan sulfate proteoglycans (HSPG), sialic acid, and terminal galactose, are recognized by specific footprints on the AAV capsid surface, typically located near the three-fold symmetry axis. For instance, AAV2 and AAV3 primarily utilize HSPG for initial cell docking, while AAV1, AAV4, and AAV5 recognize different linkages of sialic acid, and AAV9 binds to terminal galactose. This initial glycan-mediated attachment is a critical first step that concentrates the viral particles on the cell membrane, facilitating subsequent interactions with high-affinity proteinaceous co-receptors like the AAV receptor (AAVR) for internalization. In a therapeutic context, the distribution and density of these glycans across different tissues dictate the tropism and efficacy of AAV-based gene medicines such as Zolgensma and Luxturna. However, the ubiquitous nature of these glycans often leads to off-target sequestration, particularly in the liver, and can be a site for interference by pre-existing host antibodies, presenting significant challenges for precision targeting and systemic administration.

Other names

Primary AAV receptorsAAV attachment factorsHeparan sulfate proteoglycans (HSPG)Sialic acid (SIA)Terminal galactoseN-acetyl lactosamine (LacNAc)Glycosaminoglycans (GAGs)

Viral attachment and entry