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Journal of Virology, April 2002, p. 3810-3818, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3810-3818.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effects of Promyelocytic Leukemia Protein on Virus-Host Balance

Weldy V. Bonilla,^1* Daniel D. Pinschewer,^1, Paul Klenerman,² Valentin Rousson,³ Mirella Gaboli,⁴ Pier P. Pandolfi,⁴ Rolf M. Zinkernagel,¹ Maria S. Salvato,⁵ and Hans Hengartner¹

Institute of Experimental Immunology, University Hospital, CH-8091 Zurich,¹ Department of Biostatistics ISPMZ, University of Zurich, CH-8006 Zurich, Switzerland,³ Nuffield Department of Medicine, John Radcliffe Hospital, OX3 9DU Oxford, United Kingdom,² Molecular and Developmental Biology Laboratory, Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,⁴ Institute of Human Virology, University of Maryland Biotechnology Center, Baltimore, Maryland 21201⁵

Received 28 August 2001/ Accepted 11 January 2002

The cellular promyelocytic leukemia protein (PML) associates with the proteins of several viruses and in some cases reduces viral propagation in cell culture. To examine the role of PML in vivo, we compared immune responses and virus loads of PML-deficient and control mice infected with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). PML^-/- mice exhibited accelerated primary footpad swelling reactions to very-low-dose LCMV, higher swelling peaks upon high-dose inoculation, and higher viral loads in the early phase of systemic LCMV infection. T-cell-mediated hepatitis and consequent mortality upon infection with a hepatotropic LCMV strain required 10- to 100-times-lower inocula despite normal cytotoxic T-lymphocyte reactivity in PML^-/- mice. Furthermore, PML deficiency rendered mice 10 times more susceptible to lethal immunopathology upon intracerebral LCMV inoculation. Accordingly, 10-times-lower VSV inocula elicited specific neutralizing-antibody responses, a replication-based effect not observed with inactivated virus or after immunization with recombinant VSV glycoprotein. These in vivo observations corroborated our results showing more virus production in PML^-/- fibroblasts. Thus, PML is a contributor to innate immunity, defining host susceptibility to viral infections and to immunopathology.

Present address: The Scripps Research Institute, Department of Neuropharmacology, La Jolla, CA 92037.

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