Adeno-associated virus serotype 9 receptor complex (AAV9-RC)

The adeno-associated virus serotype 9 (AAV9) receptor complex is a multi-component system on the host cell surface and within endocytic pathways that mediates the entry of AAV9 viral vectors. The primary attachment factor is terminal beta-D-galactose, a glycan moiety that AAV9 capsids bind to for initial docking on the cell membrane. Following attachment, the virus requires the adeno-associated virus receptor (AAVR, or KIAA0319L), a transmembrane protein that facilitates internalization and trafficking through the endosomal system. Additional factors like G protein-coupled receptor 108 (GPR108) are essential for the virus to navigate the trans-Golgi network and reach the nucleus. This receptor complex is of paramount importance in gene therapy, as AAV9 is the delivery vehicle for FDA-approved treatments like onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy. Therapeutic strategies often involve modulating these receptors, such as using neuraminidase to remove sialic acid and expose galactose residues to enhance transduction efficiency. However, challenges remain, including pre-existing neutralizing antibodies that block receptor binding and the high sequestration of AAV9 in the liver, which can lead to off-target effects and toxicity. Understanding the structural basis of these interactions, such as the binding of the AAV9 capsid to the PKD2 domain of AAVR, is critical for engineering next-generation vectors with improved tropism.

Other names

AAV9 receptorsTerminal galactoseAdeno-associated virus receptor (AAVR)KIAA0319LG protein-coupled receptor 108 (GPR108)N-linked glycans with terminal galactosyl residuesAAV9 entry factors

AAV9 vectors utilize terminal galactose for initial cell surface attachment, followed by AAVR-mediated endocytosis and GPR108-dependent trafficking through the trans-Golgi network to the nucleus.