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: 3.1). 07/2007; 14(11):912-9. DOI: 10.1038/
Source: PubMed


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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    • "In the second approach, the knobs were tested for their capacity to directly downregulate surface CD46 expression on CD4 + T-cells, similar to what has been reported for HAdV-35 and CD46 mAbs, as well as for other viruses that bind CD46 on different cells (Adams et al., 2011; Bartz et al., 1996; Sakurai et al., 2007; Santoro et al., 1999; Schnorr et al., 1995; Yant et al., 1997). On lymphoid cells, CD46 internalizes rapidly following direct ligand binding (Crimeen-Irwin et al., 2003). "
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    ABSTRACT: The complement-regulatory protein CD46 is the primary receptor for human adenovirus type 35 (HAdV-35) and can regulate human immune-cell activation. CD4(+) T-cells are critical for initiating and maintaining adaptive immunity elicited by infection or vaccination. It was reported previously that HAdV-35 can bind these cells and suppress their activation. The data reported here demonstrate that recombinant trimeric HAdV-35 knob proteins alone can induce CD46 receptor downregulation and inhibit interleukin-2 production and proliferation of human CD4(+) T-cells in vitro similarly to mAbs specific to the CD46 region bound by HAdV-35 knobs. A mutant knob protein with increased affinity for CD46 compared with the wild-type knob caused equivalent effects. In contrast, a CD46-binding-deficient mutant knob protein did not inhibit T-cell activation. Thus, the capacity of HAdV-35 to attenuate human CD4(+) T-cell activation depends predominantly on knob interactions with CD46 and can occur independently of infection.
    Preview · Article · Feb 2012 · Journal of General Virology
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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.
    Full-text · Article · Sep 2010 · Virology
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