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Human Cytomegalovirus Induces Inhibition of Macrophage Differentiation by Binding to Human Aminopeptidase N/CD13¹

Sara Gredmark^*, William B. Britt, Xun Xie, Lennart Lindbom and Cecilia Söderberg-Nauclér^2,*

^* Department of Medicine, Center for Molecular Medicine, and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; and Department of Pediatrics and Microbiology, University of Alabama, Birmingham, AL 35233

Human CMV (HCMV) infection in immunocompromised patients is frequently associated with impaired immunological functions. We have recently found that HCMV inhibits cytokine-induced differentiation of monocytes into macrophages. In this study, we demonstrate that HCMV-induced inhibition of macrophage differentiation was dependent on binding of virus particles to the cell surface molecule CD13/aminopeptidase N, which involved Ca²⁺-dependent intracellular signaling pathways. We found that treatment of cells with the CD13-specific mAbs My7 and WM15 inhibited macrophage differentiation, and that My7 and WM15 induced a rise in intracellular Ca²⁺ in similar ways as HCMV. In contrast, binding of the CD13-specific Ab clone SJ1D1 blocked the ability of HCMV to inhibit macrophage differentiation, and blocked the HCMV-induced intracellular Ca²⁺ response. In addition, the Ca²⁺ modulator thapsigargin partially blocked the ability of HCMV to inhibit cellular differentiation. Furthermore, we demonstrate that recombinant viral glycoprotein gB was able to inhibit macrophage differentiation in similar ways as the virus. Thus, these results suggest that binding of HCMV to monocytes induces an intracellular rise of Ca²⁺, of which one result is a block in the ability of the cells to differentiate into macrophages. These observations suggest an efficient viral strategy to interfere with cellular differentiation pathways, and may also in part explain the generalized immunosuppression that is often observed in HCMV-infected patients.

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