Measles virus-induced immunosuppression in vitro is associated with deregulation of G(1) cell cycle control proteins

Virus-induced immunosuppression is the major cause of the high morbidity/mo rtality rates associated with acute measles, It has been shown previously t hat mitogen-dependent proliferation of peripheral blood lymphocytes (PBL) w as strongly impaired after contact with the measles virus (MV) glycoprotein s F and H expressed on the surface of infected cells, cells transfected wit h the corresponding expression constructs or UV-inactivated MV (UV-MV). The state of unresponsiveness was not associated with the induction of apoptos is, and a significant proportion of PBL was found to be arrested in the G(0 )/G(1) phase of the cell cycle, It is now shown that cell cycle cessation, rather than complete arrest, is induced after MV glycoprotein contact, No o bvious role was found for p53 in the induction of this unresponsiveness. Wi th UV-MV as effector, downregulation of p27, an inhibitor of cyclin-depende nt kinase (CDK)-cyclin complexes, was significantly delayed after mitogenic stimulation of human PBL, The activities of both cCDK4/6-cyclin D and CDK2 -cyclin E complexes for phosphorylation of exogenous substrates in vitro we re strongly reduced. CDK4, CDK6, cyclins D3 and E and, to a minor extent, C DK2 failed to accumulate at the protein level after mitogenic stimulation i n the presence of UV-MV, These data indicate that MV-induced proliferative unresponsiveness of PBL to mitogenic stimulation is associated with a drast ic deregulation of the expression of cell cycle genes essential for the G(1 )/S phase transition.