Adeno-associated virus receptor (AAVR) and associated glycans (AAVR/Glycans)

Adeno-associated virus receptor (AAVR) and associated glycans constitute the primary molecular machinery for the entry of AAV vectors into hepatocytes. AAVR, also known as KIAA0319-like protein (KIAA0319L), is a type I transmembrane protein with five polycystic kidney disease (PKD) domains that serves as an essential, near-universal protein receptor for most AAV serotypes, including AAV1, AAV2, AAV5, AAV8, and AAV9 (Pillay et al., 2016; nih.gov). The entry process is initiated by the binding of the viral capsid to specific cell surface glycans, which act as attachment factors; these include heparan sulfate proteoglycans (HSPG) for AAV2 and AAV3, and terminal beta-1,4-galactose for AAV9 (Bell et al., 2011; nih.gov). Following attachment, the virus engages AAVR and other co-factors like GPR108 to facilitate endocytosis and subsequent trafficking through the trans-Golgi network to the nucleus (Dudek et al., 2020; nih.gov). This receptor-glycan system is the fundamental determinant of the liver-specific tropism (hepatotropism) exploited by gene therapy vectors to treat genetic disorders such as hemophilia and metabolic diseases (nih.gov). Therapeutic agents interacting with these targets include approved gene therapies like Valoctocogene roxaparvovec and Etranacogene dezaparvovec, which rely on efficient hepatocyte entry to deliver functional transgenes (nih.gov). Challenges associated with targeting this system include the high prevalence of pre-existing neutralizing antibodies in the human population and the risk of immune-mediated hepatotoxicity following vector administration (nih.gov).

Other names

KIAA0319-like proteinKIAA0319LAAVRHeparan sulfate proteoglycansHSPGSialic acidGalactoseGPR108Laminin receptorLamR37/67-kDa laminin receptor

AAV vectors bind to primary glycan attachment factors (e.g., HSPG, galactose) and then engage proteinaceous receptors like AAVR and GPR108 to trigger endocytosis and trafficking to the nucleus for transgene expression.