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Journal of Virology, May 2002, p. 5034-5042, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.5034-5042.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of Histone Deacetylases Induces Bovine Leukemia Virus Expression In Vitro and In Vivo

C. Merezak,1 M. Reichert,2 C. Van Lint,3 P. Kerkhofs,4 D. Portetelle,5 L. Willems,1* and R. Kettmann1

Molecular and Cellular Biology,1 Animal and Microbial Biology Unit,5 Faculty of Agronomy, Gembloux, Department of Molecular Biology, IBMM, ULB, Gosselies,3 Department of Virology, Veterinary and Agrochemical Research Center, Uccle, Belgium,4 Department of Pathology, National Veterinary Research Institute, Pulawy, Poland2

Received 8 November 2001/ Accepted 26 January 2002

Packaging into nucleosomes results in a global transcriptional repression as a consequence of exclusion of sequence-specific factors. This inhibition can be relieved by using inhibitors of histone deacetylases, acetylation being a major characteristic of transcriptionally active chromatin. Paradoxically, the expression of only ~2% of the total cellular genes is modulated by histone hyperacetylation. To unravel the potential role of this transcriptional control on BLV expression, we tested the effect of two highly specific inhibitors of deacetylases, trichostatin A (TSA) and trapoxin (TPX). Our results demonstrate that treatment with TSA efficiently enhanced long terminal repeat-directed gene expression of integrated reporter constructs in heterologous D17 stable cell lines. To further examine the biological relevance of these observations made in vitro, we analyzed ex vivo-isolated peripheral blood mononuclear cells (PBMCs) from bovine leukemia virus (BLV)-infected sheep. TSA deacetylase inhibitor induced a drastic increase in viral expression at levels comparable to those induced by treatment with phorbol-12-myristate 13-acetate and ionomycin, the most efficient activators of BLV expression known to date. TSA acted directly on BLV-infected B lymphocytes to increase viral expression and does not seem to require T-cell cooperation. Inhibition of deacetylation after treatment with TSA or TPX also significantly increased viral expression in PBMCs from cattle, the natural host for BLV. Together, our results show that BLV gene expression is, like that of a very small fraction of cellular genes, also regulated by deacetylation.

* Corresponding author. Mailing address: Molecular and Cellular Biology, Faculté Universitaire des Sciences Agronomiques (FUSAGx), 13 ave. Maréchal Juin, 5030 Gembloux, Belgium. Phone: 32-81-622157. Fax: 32-81-613888. E-mail: Willems.l{at}fsagx.ac.be.

Journal of Virology, May 2002, p. 5034-5042, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.5034-5042.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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