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A Proviral Role for CpG in Cytomegalovirus Infection¹

Ann-Charlotte Iversen^2,*, Bjørg Steinkjer^*, Nadra Nilsen^*, Janne Bohnhorst^*, Siv Helen Moen^*, Randi Vik^*, Phil Stephens, David W. Thomas, Chris A. Benedict and Terje Espevik^*

^* Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Wound Biology Group, School of Dentistry, Cardiff University, Cardiff, United Kingdom; and Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

TLR9-dependent signaling in plasmacytoid dendritic cells is a key contributor to innate immune defense to mouse CMV infection. We aimed to study the expression and potential contribution of TLR9 signaling in human CMV (HCMV) infection of primary fibroblasts. HCMV infection strongly induced TLR9 expression in two of three fibroblast types tested. Furthermore, the TLR9 ligand CpG-B induced a strong proviral effect when added shortly after HCMV infection, enhancing virus production and cell viability. However, not all CpG classes displayed proviral activity, and this correlated with their IFN-β-inducing ability. The proviral effect of CpG-B correlated completely with concurrent viral up-regulation of TLR9 in fibroblasts. Importantly, the timing of CpG addition was a critical parameter; in striking contrast to the proviral effect, CpG addition at the time of infection blocked viral uptake and nearly abolished HCMV production. The contrasting and time-dependent effects of CpG on HCMV infectivity reveal a complex interplay between CpG, TLR9, and HCMV infection. Additionally, the data suggest a potentially harmful role for CpG in the promotion of HCMV infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Norwegian Cancer Society, the Central Norway Regional Health Authority, and the Commission of the European Communities, Applied Mathematics & Information Sciences, LSMH-CT-2004-512093.

² Address correspondence and reprint requests Dr. Ann-Charlotte Iversen, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Olav Kyrres gt 9, N-7489 Trondheim, Norway. E-mail address: Ann-Charlotte.Iversen{at}ntnu.no

³ Abbreviations used in this paper: HCMV, human CMV; DC, dendritic cell; IE2, immediate-early 2; LT, lymphotoxin; MCMV, mouse CMV; MOI, multiplicity of infection; NHDF, neonatal human dermal fibroblast; ODN, oligodeoxynucleotide; poly(I:C), polyinosine-polycytidylic acid; PTO, phosphorothioate; HEK, human embryonic kidney.