Replication or Persistence

Two distinguishable phases of the AAV life cycle occur in permissive or nonpermissive cells. In either case, the infecting single-stranded genome is converted to a duplex structure. There is evidence that the single-stranded genome may be converted to either linear duplexes or circular duplex molecules (79,80). However, in permissive cells in the presence of helper virus, this duplex genome then appears to follow the pathway of bulk replication using the self-priming property of the ITR to yield a large pool of head-to-head and tail-to-tail RF molecules, and ultimately a large burst of progeny particles. In nonpermissive cells in the absence of helper, these genomes follow a pathway that leads to generation of head-to-tail con-catemers that persist as episomes or become integrated into the host cell chromosome. In this nonpermissive state, there are 2 important parameters that may have different consequences for AAV or AAV vectors. In either case, there are no helper functions provided by another virus. However, for wild-type AAV, the rep gene is present and therefore may be expressed. This may explain why AAV integrates efficiently into the chromosome 19. For an AAV vector, the rep gene is not present; thus, vectors may progress through the integration pathway more slowly, or not at all, and rather follow the pathway of persistence as a circular episome (83,84).

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