After the attachment of AAV to the cell surface receptor of the target cell, the virus gets internalized by endocytosis. Depending on the serotype, different receptors and co-receptors located in the host membrane mediate the entry process. AAV2 for example can attach to heparan sulfate proteoglycan (HSPG) cell surface receptors, fibroblast growth factor receptor-1 (FGFR1), hepatocyte growth factor (HGF) receptor, and laminin receptor, whereas ανβ5 integrin and α5β1 integrin can act as co-receptors. The O-linked 2,3-sialic acid serves as a binding receptor for AAV4, whereas the N-linked sialic acid represents the binding receptors for AAV1, AAV5 & AAV6 with, for example, the platelet-derived growth factor receptor acting as a co-receptor for AAV5 internalization. AAV3, AAV8 and AAV9 have also shown that they can attach to the 37/67 kDa laminin receptor. Scientists have touched on other entry mechanisms as well, however, endocytosis is found to be the most common entry mechanism for AAV.
The clathrin-coated vesicles transport the virus through the endosome to the nucleus. Before entering the host cell nucleus, AAV needs to escape the endosome to pass the nuclear pores. The AAV endosomal escape occurs in the cytoplasm through a process that likely involves the activity of the phospholipase domain of the AAV VP1 protein.
Within the nucleus, the viral capsid sheds to release the single-stranded DNA genome which is then converted to double-stranded DNA. Until now, AAV trafficking within the cell and its transfer into the nucleus is not yet completely understood. It has been suggested that the capsid compostion of AAV plays an important role in the interaction with the target cell surface, endosomal escape, and the import into the nucleus.
After the AAV genome is uncoated inside the nucleus, the second strand synthesis occurs, converting the single stranded genome to double stranded DNA. The free end of the ITR hairpin hereby acts as a primer for the DNA synthesis. The viral DNA can then either be integrated into the host cell DNA and becomes a provirus (lysogenic cycle) or persists as episomes in a circular form (lytic cycle). The lytic life cycle of AAV is usually triggered by the presence of co-infecting helper viruses, e.g. adeno-, herpes-, human papilloma- or vaccinia viruses. The co-infection with one of the AAV helper viruses leads to the initiation of AAV gene expression, replication and the production of AAV virions. However, the predominant latent life cycle is the lysogenic cycle, which is induced by the absence of a helper virus.
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