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Diminished Intracellular Invariant Chain Expression after Vaccinia Virus Infection¹

Nan Wang^*, Ekkehard Weber and Janice S. Blum^2,*

^* Department of Microbiology and Immunology, Center for Immunobiology, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202; and Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany

Vaccinia virus (VV) has been used as a vaccine to eradicate smallpox and as a vaccine for HIV and tumors. However, the immunoevasive properties of VV have raised safety concerns. VV infection of APCs perturbs MHC class II-mediated Ag presentation. Exposure of human B cell lines to VV induced a substantial reduction in cellular expression of the class II chaperone, invariant chain (Ii), during the late stages (i.e., 8–10 h) of infection. Yet, cell viability and surface expression of MHC class II molecules were maintained up to 24 h after exposure to virus. Reductions in Ii and class II mRNA levels were detected as early as 6 h after VV infection of APCs. To examine whether VV was acting solely to disrupt host protein synthesis, B cells were treated with an inhibitor of translation, cycloheximide (CHX). Within 1 h of B cell CHX treatment, Ii protein expression decreased coupled with a loss of class II presentation. Analysis of Ii degradation in VV- or CHX-treated cells, revealed ongoing Ii proteolysis contributing to reduced steady-state Ii levels in these APC. Yet in contrast with CHX, VV infection of APCs altered lysosomal protease expression and Ii degradation. Virus infection induced cellular cathepsin L expression while reducing the levels of other lysosomal proteases. These results demonstrate that at late stages of VV infection, reductions in cellular Ii levels coupled with changes in lysosomal protease activity, contribute in part to defects in class II presentation.

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 National Institutes of Health Grants AI49589 and AI0560972, the USA Medical Research and Material Command, TATRC, and the Indiana Genomics Initiative at Indiana University School of Medicine. N.W. was supported by a fellowship for graduate studies in aging from Indiana University School of Medicine.

² Address correspondence and reprint requests to Dr. Janice S. Blum, Department of Microbiology and Immunology, Indiana Medical Science Building, Room 420, University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202. E-mail address: jblum{at}iupui.edu

³ Abbreviations used in this paper: VV, vaccinia virus; AEP, asparagine endopeptidase; AraC, arabinosylcytosine; B-LCL, B lymphoblastoid cell line; Cat, cathepsin; CHX, cycloheximide; GAD, glutamate decarboxylase; HSA, human serum albumin; HSC, heat shock cognate protein; Ii, invariant chain; Leu, leupeptin; LIP, leupeptin-induced peptide; MOI, multiplicity of infection; CLIP, class II-associated invariant chain peptide.