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Journal of Virology, September 2005, p. 11259-11268, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11259-11268.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CD46-Utilizing Adenoviruses Inhibit C/EBPß-Dependent Expression of Proinflammatory Cytokines

Milena Iacobelli-Martinez, Ronald R. Nepomuceno, Jodi Connolly, and Glen R. Nemerow^*

The Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Received 7 April 2005/ Accepted 13 June 2005

The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components C3b and C4b, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1 and -ß, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN--induced C/EBPß protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN- signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.

Present address: Isis Pharmaceuticals, Inc., 1896 Rutherford Rd., Carlsbad, CA 92008.

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