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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3722-3728.
Prepublished online as a Blood First Edition Paper on August 23, 2007; DOI 10.1182/blood-2007-04-085076.
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Submitted April 12, 2007
Accepted August 4, 2007
Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1-associated myelopathy/tropical spastic paraparesis patients
Agnes Lezin, Nicolas Gillet, Stephane Olindo, Aissatou Signate, Nathalie Grandvaux, Olivier Verlaeten, Gildas Belrose, Marcelo Carvalho Bittencourt, John Hiscott, Becca Asquith, Arsene Burny, Didier Smadja, Raymond Cesaire, and Luc Willems*
Laboratoire de Virologie-Immunologie and JE 2503, Centre Hospitalier Universitaire, Fort-de-France, Martinique, France
Molecular and Cellular Biology, University Academia "Wallonie-Europe", National Fund for Scientific Research, Gembloux, Belgium
Service de Neurologie and JE 2503, Centre Hospitalier Universitaire, Fort-de-France, Martinique, France
Department of Biochemistry, Faculty of Medicine, University of Montreal, CHUM/Hopital St Luc, Montreal, Canada
Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
Department of Immunology, Imperial College, London, United Kingdom
* Corresponding author; email: willems.l{at}fsagx.ac.be.
Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the Human T-lymphotropic virus type 1 which is responsible for HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches which focus on reducing either cell proliferation, viral replication or tissue invasion, are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression in order to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor which has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/ as #NCT00519181.
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