Document Detail


Impact of adenovirus life cycle progression on the generation of canine helper-dependent vectors.
MedLine Citation:
PMID:  25338917     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Helper-dependent adenovirus vectors (HDVs) are safe and efficient tools for gene transfer with high cloning capacity. However, the multiple amplification steps needed to produce HDVs hamper a robust production process and in turn the availability of high-quality vectors. To understand the factors behind the low productivity, we analyzed the progression of HDV life cycle. Canine adenovirus (Ad) type 2 vectors, holding attractive features to overcome immunogenic concerns and treat neurobiological disorders, were the focus of this work. When compared with E1-deleted (ΔE1) vectors, we found a faster helper genome replication during HDV production. This was consistent with an upregulation of the Ad polymerase and pre-terminal protein and led to higher and earlier expression of structural proteins. Although genome packaging occurred similarly to ΔE1 vectors, more immature capsids were obtained during HDV production, which led to a ~4-fold increase in physical-to-infectious particles ratio. The higher viral protein content in HDV-producing cells was also consistent with an increased activation of autophagy and cell death, in which earlier cell death compromised volumetric productivity. The increased empty capsids and earlier cell death found in HDV production may partially contribute to the lower vector infectivity. However, an HDV-specific factor responsible for a defective maturation process should be also involved to fully explain the low infectious titers. This study showed how a deregulated Ad cycle progression affected cell line homeostasis and HDV propagation, highlighting the impact of vector genome design on virus-cell interaction.Gene Therapy advance online publication, 23 October 2014; doi:10.1038/gt.2014.92.
Authors:
P Fernandes; D Simão; M R Guerreiro; E J Kremer; A S Coroadinha; P M Alves
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-23
Journal Detail:
Title:  Gene therapy     Volume:  -     ISSN:  1476-5462     ISO Abbreviation:  Gene Ther.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-23     Completed Date:  -     Revised Date:  2014-10-24    
Medline Journal Info:
Nlm Unique ID:  9421525     Medline TA:  Gene Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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