The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy

TLDR

AAV is a gene‑therapy vector whose capsid has a beta‑barrel fold and unique surface loops, including threefold‑related peaks that influence receptor attachment and antibody recognition. The structure will guide rational engineering of vector capsids to tailor cellular targeting and avoid immediate neutralization by an immune system sensitized by prior exposure to AAV. The 3‑Å crystal structure of AAV‑2 shows that cell‑entry and receptor‑binding mutations cluster near positively charged peaks on the capsid surface, implicating these loops in attachment to heparan sulfate proteoglycan and antibody recognition.

Abstract

The structure of the adeno-associated virus (AAV-2) has been determined to 3-A resolution by x-ray crystallography. AAV is being developed as a vector for gene therapy to treat diseases including hemophilia, cancer, and cystic fibrosis. As in the distantly related autonomous parvoviruses, the capsid protein has a beta-barrel fold, but long loops between the beta-strands share little structural homology with other parvoviruses, leading to unique surface features. Most prominent are groups of threefold-related peaks, each an intimate association of loops from two neighboring subunits. Mutations affecting cell entry and receptor binding are clustered near the positively charged side of each peak, implicating the region in attachment to the cellular receptor, heparan sulfate proteoglycan. Amino acids involved in antibody binding are in the same general vicinity. The structure will guide rational engineering of vector capsids to tailor cellular targeting and to avoid immediate neutralization by an immune system sensitized by prior exposure to AAV.