Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle

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...

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Bibliographic Details
Published in:Viruses 2021-06, Vol.13 (6), p.1185
Main Authors: Zhang, Junping, Yu, Xiangping, Guo, Ping, Firrman, Jenni, Pouchnik, Derek, Diao, Yong, Samulski, Richard Jude, Xiao, Weidong
Format: Article
Language:English
Subjects:
adeno-associated virus
Capsid Proteins - genetics
Defective Interfering Viruses - genetics
Defective Interfering Viruses - growth & development
Dependovirus - genetics
Dependovirus - growth & development
Double-stranded RNA
Encapsidation
Gene expression
Genes
Genetic engineering
Genome, Viral
Genomes
HEK293 Cells
Humans
Infections
life cycle
Life Cycle Stages - genetics
Life cycles
Monoclonal antibodies
Packaging
Plasmids
Proteins
Rep gene
subgenomic particles
Transcription
Viral Proteins - genetics
Virion - metabolism
Virions
Virus Replication
Viruses
“snapback” configuration
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Summary: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 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.
ISSN:1999-4915
1999-4915
DOI:10.3390/v13061185