Adeno-associated virus receptor complexes and implications for adeno-associated virus immune neutralization

Adeno-associated viruses (AAV) are among the foremost vectors for in vivo gene therapy. A number of monoclonal antibodies against several serotypes of AAV have previously been prepared. Many are neutralizing, and the predominant mechanisms have been reported as the inhibition of binding to extracellular glycan receptors or interference with some post-entry step. The identification of a protein receptor and recent structural characterization of its interactions with AAV compel reconsideration of this tenet. AAVs can be divided into two families based on which domain of the receptor is strongly bound. Neighboring domains, unseen in the high-resolution electron microscopy structures have now been located by electron tomography, pointing away from the virus. The epitopes of neutralizing antibodies, previously characterized, are now compared to the distinct protein receptor footprints of the two families of AAV. Comparative structural analysis suggests that antibody interference with protein receptor binding might be the more prevalent mechanism than interference with glycan attachment. Limited competitive binding assays give some support to the hypothesis that inhibition of binding to the protein receptor has been an overlooked mechanism of neutralization. More extensive testing is warranted.