Diminished Intracellular Invariant Chain Expression after Vaccinia Virus Infection

Abstract

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.