Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.

A. Lezin, N. Gillet, S. Olindo, A. Signate, N. Grandvaux, O. Verlaeten, G. Belrose, M. de Carvalho Bittencourt, J. Hiscott, B. Asquith, Arsène Burny, D. Smadja, R. Cesaire, L. Willems

Research output: Contribution to journalArticle

Abstract

[en] Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-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 that 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 to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that 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 no. NCT00519181.
Original languageEnglish
JournalBlood
Volume110
Issue number10
DOIs
Publication statusPublished - 2007
Externally publishedYes

Keywords

  • Sciences de la santé humaine => Oncologie
  • Enzyme Inhibitors/pharmacology
  • Gene Expression Regulation, Viral/drug effects
  • HeLa Cells
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases/physiology
  • Human T-lymphotropic virus 1/growth development
  • Humans
  • Jurkat Cells
  • Paraparesis, Tropical Spastic/genetics/virology
  • Proviruses/growth development
  • Transcriptional Activation/physiology
  • Transfection
  • Valproic Acid/pharmacology
  • Viral Load

Fingerprint Dive into the research topics of 'Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.'. Together they form a unique fingerprint.

  • Cite this

    Lezin, A., Gillet, N., Olindo, S., Signate, A., Grandvaux, N., Verlaeten, O., Belrose, G., de Carvalho Bittencourt, M., Hiscott, J., Asquith, B., Burny, A., Smadja, D., Cesaire, R., & Willems, L. (2007). Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. Blood, 110(10). https://doi.org/10.1182/blood-2007-04-085076