Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins.

Abstract

Virus-induced immunosuppression is the major cause of the high morbidity/mortality rates associated with acute measles. It has been shown previously that mitogen-dependent proliferation of peripheral blood lymphocytes (PBL) was strongly impaired after contact with the measles virus (MV) glycoproteins F and H expressed on the surface of infected cells, cells transfected with the corresponding expression constructs or UV-inactivated MV (UV-MV). The state of unresponsiveness was not associated with the induction of apoptosis, 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 obvious role was found for p53 in the induction of this unresponsiveness. With UV-MV as effector, downregulation of p27, an inhibitor of cyclin-dependent kinase (CDK)-cyclin complexes, was significantly delayed after mitogenic stimulation of human PBL. The activities of both CDK4/6-cyclin D and CDK2-cyclin E complexes for phosphorylation of exogenous substrates in vitro were strongly reduced. CDK4, CDK6, cyclins D3 and E and, to a minor extent, CDK2 failed to accumulate at the protein level after mitogenic stimulation in the presence of UV-MV. These data indicate that MV-induced proliferative unresponsiveness of PBL to mitogenic stimulation is associated with a drastic deregulation of the expression of cell cycle genes essential for the G 1 /S phase transition.

Measles virus inhibits human immunodeficiency virus type 1 reverse transcription and replication by blocking cell-cycle progression of CD4+ T lymphocytes

“…Decreased levels of the cyclins D1, D3 and E were observed after co-culture of PBMCs with Chicago-1 MV or co-culture of PBMCs with Chicago-1 MV and HIV-1 BaL (Fig. 4a), consistent with a block in cell-cycle progression into the S phase induced by MV (Engelking et al, 1999;Heaney et al, 2002;Naniche et al, 1999).…”

“…Inhibition of lymphoproliferation by MV in the cotton rat model is associated with retardation of the cell cycle in G 0 /G 1 (Niewiesk et al, 1999). Arrested lymphoproliferation in the G 0 /G 1 phase of the cell cycle after infection with MV or contact with MVinfected cells is associated with reduced expression and activity of G 1 cyclin-dependent kinase complexes and delayed degradation of p27 kip (Engelking et al, 1999). Cyclin D1 regulates progression of cells through G 1 /S phase (Stacey, 2003) and downregulation of cyclin D1 by MV has not been described previously.…”

Lymphoid Apoptosis in Acute Canine Distemper

“…Similar events may also occur to cause immune suppression and persistent CDV-infection in the dogs of group 2. Recently, it has been suggested MV-induced immunosuppression is due to cell cycle arrest in the G 0 /G 1 phase of uninfected lymphocytes after contracted with MV glycoprotein activating on surface of MV-infected cells [3,16,17,20,26]. The cell cycle arrest is suggested to be associated with low accumulation levels of cyclin D3 and E, low activity of G 1 cyclin-dependent kinase, and accumulation of CDK inhibitor, p27 Kip1 .…”

Expansion of human γ/δ T cells in vitro is differentially regulated by the measles virus glycoproteins

“…Negative signalling by the effector complex did not prime for or induce T cell apoptosis, but rather caused a strongly retarded passage of the G 1 /S phase restriction point after mitogenic stimulation (Niewiesk et al, 1999;Schnorr et al, 1997a cyclin-associated kinases and p27 Kip1 were seen (Engelking et al, 1999). In spite of their nonproliferating state, mitogen-stimulated T cells produced normal levels of cytokines, including IL-2, and upregulated early activation markers, also including the IL-2R a-subunit (CD25).…”