Antibodies bound to AAV particles are recognized by the complement protein C1 complex. When high doses of AAV are administered, AAV-antibody complex activates the classical pathway of complement, eventually leading to the formation of the membrane attack complex (MAC) (105). The target of the MAC ring during AAV infection is unclear. When low AAV doses are administered, C3b can bind to the AAV capsid, where it is converted to iC3b and subsequently to C3d by factor I and other cofactors. Cleavage fragments of C3 opsonize the target structure and serve as bridging molecules with receptors on the surface of the phagocytes. CR1 and CR3 expressed on the macrophage surface interact with C3b- or iC3b-opsonized AAV particles, leading to phagocytosis and macrophage activation. CR3 interaction with iC3b-opsonized AAV virions on DC surfaces also results in endocytosis and antigen presentation to naive T cells. C3d-bound AAVs can be recognized by CR2 on B cell surfaces. Co-ligation of CR2 with B cell receptor (BCR) results in augmented signaling that effectively lowers the threshold for B cell clonal expansion. Alternatively, DCs can also trap the C3d-opsonized AAV via CR2 and present the antigen to naive or previously antigen-engaged B cells during the processes of affinity maturation, isotype switching, and the generation of effector and memory B cells.