Abstract
Historically, adeno-associated virus (AAV)-defective interfering particles (DI) were known as abnormal virions arising from natural replication and encapsidation errors. Through single virion genome analysis, we revealed that a major category of DI particles contains a double-stranded DNA genome in a “snapback” configuration. The 5′- snapback genomes (SBGs) include the P5 promoters and partial rep gene sequences. The 3′-SBGs contains the capsid region. The molecular configuration of 5′-SBGs theoretically may allow double-stranded RNA transcription in their dimer configuration. Our studies demonstrated that 5-SBG regulated AAV rep expression and improved AAV packaging. In contrast, 3′-SBGs at its dimer configuration increased levels of cap protein. The generation and accumulation of 5′-SBGs and 3′-SBGs appears to be coordinated to balance the viral gene expression level. Therefore, the functions of 5′-SBGs and 3′-SBGs may help maximize the yield of AAV progenies. We postulate that AAV virus population behaved as a colony and utilizes its subgenomic particles to overcome the size limit of a viral genome and encodes additional essential functions.
Highlights
associated virus (AAV) is a replication-defective parvovirus which requires a helper virus to complete its life cycle [1]
In contrast to the general belief that all subgenomic particles are waste-byproducts and only compete for essential resources required for wild type virus replication and packaging, our findings suggest that the AAV virus has evolved to utilize these subgenomic particles to potentially encode dsRNA that regulate rep expression and augment cap expression
Category 1: Canonical AAV genomes, which contain the full AAV genome flanked by two copies of the AAV inverted terminal repeats (ITR); Both positive and negative strands are encapsidated into AAV capsids
Summary
AAV is a replication-defective parvovirus which requires a helper virus to complete its life cycle [1]. The virus is best known for its small genome, which is tightly packaged inside a capsid that is 20–25 nm in diameter. Its single-stranded DNA genome contains approximately 4700 nucleotides and encodes the rep and cap genes which represent the non-structural and capsid proteins, respectively. AAV replication is mediated by the rep proteins, which are capable of nicking the inverted terminal repeats (ITR) and initiates AAV replication. In the presence of a helper virus, AAV undergoes its lytic infection. AAV integrates into the host genome and maintains a relatively stable, latent state
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