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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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Autores principales: Zhang, Junping, Yu, Xiangping, Guo, Ping, Firrman, Jenni, Pouchnik, Derek, Diao, Yong, Samulski, Richard Jude, Xiao, Weidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235507/
https://www.ncbi.nlm.nih.gov/pubmed/34205760
http://dx.doi.org/10.3390/v13061185
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author Zhang, Junping
Yu, Xiangping
Guo, Ping
Firrman, Jenni
Pouchnik, Derek
Diao, Yong
Samulski, Richard Jude
Xiao, Weidong
author_facet Zhang, Junping
Yu, Xiangping
Guo, Ping
Firrman, Jenni
Pouchnik, Derek
Diao, Yong
Samulski, Richard Jude
Xiao, Weidong
author_sort Zhang, Junping
collection PubMed
description 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.
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spelling pubmed-82355072021-06-27 Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle Zhang, Junping Yu, Xiangping Guo, Ping Firrman, Jenni Pouchnik, Derek Diao, Yong Samulski, Richard Jude Xiao, Weidong Viruses Article 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. MDPI 2021-06-21 /pmc/articles/PMC8235507/ /pubmed/34205760 http://dx.doi.org/10.3390/v13061185 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Junping
Yu, Xiangping
Guo, Ping
Firrman, Jenni
Pouchnik, Derek
Diao, Yong
Samulski, Richard Jude
Xiao, Weidong
Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle
title Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle
title_full Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle
title_fullStr Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle
title_full_unstemmed Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle
title_short Satellite Subgenomic Particles Are Key Regulators of Adeno-Associated Virus Life Cycle
title_sort satellite subgenomic particles are key regulators of adeno-associated virus life cycle
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235507/
https://www.ncbi.nlm.nih.gov/pubmed/34205760
http://dx.doi.org/10.3390/v13061185
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