Role of the promyelocytic leukemia protein PML in the interferon sensitivity of lymphocytic choriomeningitis virus

Lymphocytic choriomeningitis virus (LCMV) induces type I interferon (alpha and beta interferon [IFN-alpha and IFN-beta]) upon infection and yet is sen sitive to the addition of type II interferon (gamma interferon [IFN-gamma]) to the culture media, This sensitivity is biologically important because i t correlates inversely with the ability of certain LCMV strains to persist in mice (D, Moskophidis, M. Battegay, M. A. Bruendler, E. Laine, I. Gresser , and R, M, Zinkernagel, J, Virol, 68:1951-1955, 1994), The cellular oncopr otein PML is induced by both LFN-alpha/beta and IFN-gamma, and PML binds th e LCMV Z protein and becomes redistributed within cells from nucleus to cyt oplasm upon LCMV infection. In the present study, increased PML expression results in diminished LCMV replication, implicating PML in the IFN sensitiv ity of LCMV. Virus production in PML -/- murine embryonic fibroblasts (MEF) exceeds virus production in PML +/+ MEF, and this difference is exacerbate d by IFN treatment that upregulates PML expression, IFN-gamma also diminish es LCMV production in PML -/- cells; therefore, viral IFN sensitivity is no t entirely due to PML. Both viral mRNA production and viral protein product ion decrease as PML expression increases, Here we propose that PML reduces LCMV transcription through its interaction with the Z protein.