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Downregulation of human CD46 by adenovirus serotype 35 vectors
F Sakurai1, K Akitomo, K Kawabata
1Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan.
Abstract:
Human CD46 (membrane cofactor protein), which serves as a receptor for a variety of pathogens, including strains of measles virus, human herpesvirus type 6 and Neisseria, is rapidly downregulated from the cell surface following infection by these pathogens. Here, we report that replication-incompetent adenovirus (Ad) serotype 35 (Ad35) vectors, which belong to subgroup B and recognize human CD46 as a receptor, downregulate CD46 following infection. A decline in the surface expression of CD46 in human peripheral blood mononuclear cells was detectable 6 h after infection, and reached maximum (72%) 12 h after infection. Ad35 vector-induced downregulation of surface CD46 levels gradually recovered after the removal of Ad35 vectors, however, complete recovery of CD46 expression was not observed even at 96 h after removal. The surface expression of CD46 was also reduced after incubation with fiber-substituted Ad serotype 5 (Ad5) vectors bearing Ad35 fiber proteins, ultraviolet-irradiated Ad35, vectors and recombinant Ad35 fiber knob proteins; in contrast, conventional Ad5 vectors did not induce surface CD46 downregulation, suggesting that the fiber knob protein of Ad35 plays a crucial role in the downregulation of surface CD46 density. These results have important implications for gene therapy using CD46-utilizing Ad vectors and for the pathogenesis of Ads that interact with CD46.
Insights
Adenovirus serotype 35 (Ad35) vectors downregulate human CD46 (membrane cofactor protein) cell surface expression. The Ad35 fiber knob protein is crucial for this CD46 downregulation, impacting gene therapy and viral pathogenesis.
Area of Science:
- Virology
- Immunology
- Gene Therapy
Background:
- Human CD46 (membrane cofactor protein) is a cell surface receptor for pathogens like measles virus and Neisseria.
- Pathogen binding typically leads to rapid CD46 downregulation from the cell surface.
Purpose of the Study:
- To investigate the effect of replication-incompetent adenovirus serotype 35 (Ad35) vectors on human CD46 surface expression.
- To identify the viral component responsible for Ad35-mediated CD46 downregulation.
Main Methods:
- Infection of human peripheral blood mononuclear cells (PBMCs) with Ad35 vectors.
- Quantification of CD46 surface expression using flow cytometry at various time points post-infection.
- Incubation with modified Ad vectors (Ad5 bearing Ad35 fibers, UV-inactivated Ad35, Ad35 fiber knob proteins) and conventional Ad5 vectors.
Main Results:
- Ad35 vectors significantly downregulated CD46 surface expression on PBMCs, with maximum reduction observed at 12 hours post-infection.
- CD46 expression showed partial recovery after Ad35 vector removal, but complete recovery was not achieved within 96 hours.
- Downregulation was mediated by Ad35 fiber proteins, specifically the fiber knob, as Ad5 vectors with Ad35 fibers and recombinant Ad35 fiber knob proteins induced similar effects, while conventional Ad5 vectors did not.
Conclusions:
- The fiber knob protein of Ad35 is critical for the downregulation of CD46 surface expression.
- These findings have significant implications for the use of CD46-utilizing Ad vectors in gene therapy.
- Understanding this interaction is important for elucidating the pathogenesis of adenoviruses that engage CD46.
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