Article

Downregulation of human CD46 by adenovirus serotype 35 vectors

Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan.
Gene Therapy (Impact Factor: 4.2). 07/2007; 14(11):912-9. DOI: 10.1038/sj.gt.3302946
Source: PubMed

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.

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    • "These vectors use coxsackievirus B-adenovirus receptor (CAR) for entry into host cells. In contrast, serotype 35 (Ad35), which belongs to subgroup B, utilizes CD46 receptor that is expressed ubiquitously on all nucleated human cells, and greatly upregulated in malignant tumor cells [1] [2] [3]. The tropism of an adenovirus is mainly determined by its fiber, and many reports have demonstrated that a chimeric adenovirus that preserves the binding function of wild type Ad35 is a better anticancer vector and even has less toxicity compared to Ad5 [4] [5]. "
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    • "We have also demonstrated that the cell surface levels of CD55 and CD59 down-regulation vary greatly in various cell lines and at different time points p.i. Ad11p virions induced a more effective downregulation in the K562 cells of hematopoietic origin than in the epithelial A549 cells. These results are in agreement with the results of previous studies on downregulation of CD46 expression by Ad35 (Sakurai i et al., 2007), whereas the moderate effect with Ad7p perhaps provides a clue to the biological relevance of low-affinity binding to CD46. "
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    ABSTRACT: Adenovirus 11 prototype (Ad11p), belonging to species B, uses CD46 as an attachment receptor. CD46, a complement regulatory molecule, is expressed on all human nucleated cells. We show here that Ad11p virions downregulate CD46 on the surface of K562 cells as early as 5min p.i. Specific binding to CD46 by the Ad11p fiber knob was required to mediate downregulation. The complement regulatory factors CD55 and CD59 were also reduced to a significant extent as a consequence of Ad11p binding to K562 cells. In contrast, binding of Ad7p did not result in downregulation of CD46 early in infection. Thus, the presumed interaction between Ad7p and CD46 did not have the same consequences as the Ad11p-CD46 interaction, the latter virus (Ad11p) being a promising gene therapy vector candidate. These findings may lead to a better understanding of the pathogenesis of species B adenovirus infections.
    Virology 09/2010; 405(2):474-82. DOI:10.1016/j.virol.2010.06.026 · 3.28 Impact Factor
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    • "These vectors use coxsackievirus B-adenovirus receptor (CAR) for entry into host cells. In contrast, serotype 35 (Ad35), which belongs to subgroup B, utilizes CD46 receptor that is expressed ubiquitously on all nucleated human cells, and greatly upregulated in malignant tumor cells [1] [2] [3]. The tropism of an adenovirus is mainly determined by its fiber, and many reports have demonstrated that a chimeric adenovirus that preserves the binding function of wild type Ad35 is a better anticancer vector and even has less toxicity compared to Ad5 [4] [5]. "
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    ABSTRACT: Chimeric adenoviral vectors possessing fiber derived from human adenovirus subgroup B (Ad35) have been developed for their high infection efficiency in cell types which are refractory to adenovirus serotype 5 (Subgroup C). The present study constructed an E1B-deleted chimeric oncolytic adenovirus, SG235-TRAIL, which carries a human TRAIL gene expression cassette and whose fiber shaft and knob domains are from serotype Ad35. It was found that SG235-TRAIL preferentially replicated in gastric cancer cell lines, SGC-7901 and BGC-823 compared to in normal human fibroblast BJ cells. Also, when compared with a replication-deficient chimeric vector Ad5/35-TRAIL, SG235-TRAIL mediated a higher level of the transgene expression via viral replication in the cancer cells. Further, because of the more efficient cell-entry and infection, SG235-TRAIL induced stronger cell apoptosis than the Ad5 CRAD vector, ZD55-TRAIL. In addition, SG235-TRAIL in combination with the chemotherapeutic drug, taxol, produced a synergistic cytotoxic effect in cancer cells in vitro without causing significant toxicity to normal cells. In the gastric tumor xenograft mouse model, intratumoral SG235-TRAIL injection produced a significant antitumor effect 14 days after treatment. Pathological examination demonstrated TRAIL expression and associated apoptosis in majority of SG235-TRAIL-treated tumor cells. These results suggest that SG235-TRAIL is a potential novel, efficient anti-cancer agent, and in combination with taxol, it would be even more useful with considerably low toxic side effects.
    Cancer letters 06/2009; 284(2):141-8. DOI:10.1016/j.canlet.2009.04.026 · 5.62 Impact Factor
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