Role of the AAV Receptor in AAV Cell Entry and Trafficking
Adeno-associated virus (AAV) has emerged as a promising delivery platform for gene therapies due to its relative safety and potential for long-term efficacy. However, the use of AAV is limited by its broad tropism and neutralizability, both related to the cellular AAV receptor (AAVR)- AAVR is ubiquitously expressed, and AAVR-binding residues on the AAV capsid are commonly recognized by the immune system. AAVR is required for cell entry but its interactions with AAV are not well understood. Increased knowledge of the role of AAVR will allow for rational design of AAV capsids to improve safety and expand use while retaining function. This project asks whether the role of AAVR in transduction is passive, a means for AAV to enter the correct trafficking pathway; or active, where binding-induced structural changes are necessary. To this end, modified versions of AAV2 and AAVR which don't interact on their own were artificially targeted to each other through complementary peptide tag and nanobody insertions. Preliminary results suggest that artificial targeting does not rescue AAV transduction. Further studies are needed to identify the step at which transduction is unsuccessful for the artificially-targeted variants and how AAVR contributes to AAV transduction.