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bioRxiv · 10.1101/2022.01.23.477411

Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors

Xu, G.·Zhang, R.·Li, H.·Yin, K.·Ma, X.·Lou, Z.
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Abstract

Clade F adeno-associated virus (AAV) 9 has been utilized as therapeutic gene delivery vector, and it is capable of crossing blood brain barrier (BBB). Recently, an AAV9 based engineering serotype with enhanced BBB crossing ability, AAVPHP.eB, further expand clade F AAVs usages in the central nervous system (CNS) gene delivery. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the AAVPHP.eB, and its parental serotype AAV9 alone or in complex with their essential receptor Adeno-associated virus receptor (AAVR). These structures reveal the molecular details of their AAVR recognition, where the polycystic kidney disease (PKD) repeat domain 2 (PKD2) of AAVR interact to the 3-fold protrusions and the raised capsid regions between the 2- and 5-fold axes termed the 2/5-fold wall of both AAV9 and AAVPHP.eB virions. The interacting patterns of AAVR to AAV9 and AAVPHP.eB are similar with what was observed in AAV1/AAV2-AAVR complexes. Moreover, we found that AAVPHP.eB variable region VIII (VR-VIII) may independently facilitate the new receptor recognition responsible for enhanced CNS transduction. Our study provides insights into different receptor recognition for engineered AAVPHP.eB and parental serotype AAV9, and further reveal the potential molecular basis underlying their different tropism.

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Xu, G., Zhang, R., Li, H., Yin, K., Ma, X., Lou, Z.. 2022-01-24. Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors. https://doi.org/10.1101/2022.01.23.477411

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