Abstract
Adenoviruses are efficient vehicles for transducing airway epithelial cells. Human adenoviruses (Ads) are classified into seven species termed A–G. Most species use the coxsackie-adenovirus receptor (CAR) as a primary cellular receptor. Ad group B is notable because it is further divided into groups B1 and B2 and its members use CD46 or desmoglein 2 (DSG2) as cellular receptors. To date, human Ad types 2 and 5 have been the predominant choices for preclinical and clinical trials using Ad-based viral vectors in the airways. In this study, we screened 14 Ad types representing species C, B1, B2, D, and E. Using well-differentiated primary cultures of human airway epithelial cells (HAEs), we examined transduction efficiency. Based on GFP or nanoluciferase expression, multiple Ad types transduced HAEs as well as or better than Ad5. Ad3, Ad21, and Ad14 belong to species B and had notable transduction properties. We further examined the transduction properties of conditionally reprogrammed airway basal cells and primary basal cells from human lung donors. Again, the transduction efficiency of species B members outperformed the other types. These data suggest that adenoviral vectors based on species B transduce fully differentiated epithelial cells and progenitor cells in the human airways better than Ad5.
Highlights
Adenoviruses are a diverse family of double-stranded DNA viruses that are associated with a variety of human diseases
Transduction of Well-Differentiated Primary Cultures of Airway Epithelial Cells Our initial studies addressed three questions: (1) which Ad types efficiently transduce well-differentiated primary cultures of human airway epithelial cells (HAEs); (2) when does transgene expression reach a peak after cell transduction; and (3) are there Ad types that preferentially transduce the apical surface? As indicated, the Ad vectors were applied to the basolateral (Figure 1C) or apical (Figure 1D) surface of HAEs at an MOI of 50 for 4 h
Ad5 is commonly used for many gene transfer applications; the adenovirus family has many members that vary greatly in their tissue tropism and pathologies
Summary
Adenoviruses are a diverse family of double-stranded DNA viruses that are associated with a variety of human diseases. Ad-based viral vectors are rendered replication incompetent by deleting virally encoded genes and complementing the deletions in producer cells in trans. The extent of viral genome deletion ranges from the E1 region alone (first generation) to complete deletion of all virally encoded proteins (helper-dependent Ad [HDAd]). The human adenovirus nomenclature is abbreviated for each Ad-based vector; for example, vectors derived from HAdV-C5 are referred to as Ad5. Viral vectors derived from species C efficiently transduce many airway epithelial cell types, including ciliated, nonciliated, basal, goblet, and submucosal gland cells.[1,2] there may be better choices for airway gene transfer. Biomedical research has explored only a small fraction of Ads, and improvements in Ad taxonomy and genome availability provide an opportunity to explore diverse Ad types as gene delivery vectors.[3]
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