Proteolytic cleavage of the fusion protein but not membrane fusion is required for measles virus-induced immunosuppression in vitro

Immunosuppression induced by measles virus (MV) is associated with unrespon siveness of peripheral blood lymphocytes (PBL) to mitogenic stimulation ex vivo and in vitro. In mixed lymphocyte cultures and in an experimental anim al model, the expression of the MV glycoproteins on the surface of UV-inact ivated MV particles, MV-infected cells, or cells transfected to coexpress t he MV fusion (F) and the hemagglutinin (H) proteins was found to be necessa ry and sufficient for this phenomenon. We now show that MV fusion-inhibitor y peptides do not interfere with the induction of immunosuppression in vitr o, indicating that MV F-H-mediated fusion is essentially not involved in th is process. Proteolytic cleavage of MV F-0 protein by cellular proteases, s uch as furin, into the F-1-F-2 subunits is, however, an absolute requiremen t, since (i) the inhibitory activity of MV-infected BJAB cells was signific antly impaired in the presence of a furin-inhibitory peptide and (ii) cells expressing or viruses containing uncleaved F-0 proteins revealed a strongl y reduced inhibitory activity which was improved following trypsin treatmen t. The low inhibitory activity of effector structures containing mainly F-0 proteins was not due to an impaired F-0-H interaction, since both surface expression and cocapping efficiencies were similar to those found with the authentic MV F and H proteins. These results indicate that the fusogenic ac tivity of the MV F-H complexes can be uncoupled from their immunosuppressiv e activity and that the immunosuppressive domains of these proteins are exp osed only after proteolytic activation of the MV F-0 protein.