Cell cycle arrest during measles virus infection: a G0-like block leads to suppression of retinoblastoma protein expression.
One of the major mechanisms by which measles virus (MV) infection causes disease and death is suppression of the immune response. The nonresponsiveness of MV-infected human lymphocytes to mitogens and a partial block in the G0/G1 phase of the cell cycle observed in vitro is thought to reflect in vivo immunosuppression. In order to molecularly dissect MV-induced immunosuppression, we analyzed expression of surface activation markers and cell cycle-regulatory proteins in MV-infected human T lymphocytes. MV Edmonston (MV-Ed) could induce and maintain a high level of the early activation marker CD69 in the absence of proliferation. Expression of cyclins D3 and E, which positively control entry into S phase, was also significantly decreased. Analysis of inhibitors of progression into S phase showed that a high level of p27 was maintained in the G0/G1-blocked subpopulation of MV-Ed-infected cells compared to the proliferating MV-infected cells. Furthermore, cell cycle-related upregulation of retinoblastoma (Rb) protein synthesis did not occur in the MV-Ed-infected lymphocytes. Acridine orange staining, which distinguishes cells in G0 from cells in G1, showed that RNA levels were not upregulated following activation, which is consistent with cells remaining in a G0 state. Although expression of surface activation markers indicated entry into the cycle, intracellular Rb and RNA levels suggested a quiescent state. These results indicate that MV can uncouple activation of T lymphocytes from transition of G0 to G1.
Naniche
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Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA. naniche@scripps.edu
Reed
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Oldstone
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MB
D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D056743:Cyclin D3; D016213:Cyclins / Q000032:analysis; D016193:G1 Phase; D006801:Humans; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008457:Measles / Q000276:immunology* / Q000378:metabolism; D008840:Microfilament Proteins / Q000032:analysis; D009124:Muscle Proteins; D012335:RNA, Ribosomal / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000096:biosynthesis*; D000099192:CD69 Antigens