The Genetics of Adeno-Associated Virus

Adeno-associated virus (AAV) is a defective parvovirus which is absolutely dependent on coinfection with a helper virus for a productive lytic cycle (for a review, see ref. 1). Either adenoviruses or herpes viruses can act as helpers (2–5) . In the absence of a helper virus, AAV efficiently integrates into host cell chromosomes via its inverted terminal repeats (6, 7). Integrated AAV genomes are essentially genetically stable and do not express their genes (8). An interesting feature of AAV biology is the fact that when a cell line that is latently infected with AAV is superinfected with a helper virus, the integrated AAV genome is rescued and proceeds through a normal lytic cycle (6, 8). It is likely that the inverted terminal repeats of AAV are involved in the rescue of the genome as well as its integration, but as yet relatively little is known about these processes. There is substantial evidence, however, to support the idea that the AAV terminal repeat is the origin for DNA replication (1, 9–11) and a reasonable model (1, 9) which describes the mode of AAV DNA replication has been proposed (Figure 1). In the model the terminal repeat, which contains palindromic sequences, acts as a hairpin primer to initiate DNA replication. The hairpin is resolved by cleavage of the parental strand opposite the primer position.