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

Fingerprint

Tropical Spastic Paraparesis
Histone Deacetylases
Spinal Cord Diseases
Viruses
Transcriptional Activation
Chemical activation
Histone Deacetylase Inhibitors
Cell proliferation
Valproic Acid
Neurology
Pathogens
Gene expression
Virus Latency
Chromatin
Antiviral Agents
Virus Activation
Human T-lymphotropic virus 1
Blood
Viral Genes
Genes

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

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, Arsène ; Smadja, D. ; Cesaire, R. ; Willems, L. / Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. In: Blood. 2007 ; Vol. 110, No. 10.
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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.",
keywords = "Sciences de la sant{\'e} 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",
author = "A. Lezin and N. Gillet and S. Olindo and A. Signate and N. Grandvaux and O. Verlaeten and G. Belrose and {de Carvalho Bittencourt}, M. and J. Hiscott and B. Asquith and Ars{\`e}ne Burny and D. Smadja and R. Cesaire and L. Willems",
year = "2007",
doi = "10.1182/blood-2007-04-085076",
language = "English",
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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, vol. 110, no. 10. https://doi.org/10.1182/blood-2007-04-085076

Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. / Lezin, A.; Gillet, N.; Olindo, S.; Signate, A.; Grandvaux, N.; Verlaeten, O.; Belrose, G.; de Carvalho Bittencourt, M.; Hiscott, J.; Asquith, B.; Burny, Arsène; Smadja, D.; Cesaire, R.; Willems, L.

In: Blood, Vol. 110, No. 10, 2007.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.

AU - Lezin, A.

AU - Gillet, N.

AU - Olindo, S.

AU - Signate, A.

AU - Grandvaux, N.

AU - Verlaeten, O.

AU - Belrose, G.

AU - de Carvalho Bittencourt, M.

AU - Hiscott, J.

AU - Asquith, B.

AU - Burny, Arsène

AU - Smadja, D.

AU - Cesaire, R.

AU - Willems, L.

PY - 2007

Y1 - 2007

N2 - [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.

AB - [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.

KW - Sciences de la santé humaine => Oncologie

KW - Enzyme Inhibitors/pharmacology

KW - Gene Expression Regulation, Viral/drug effects

KW - HeLa Cells

KW - Histone Deacetylase Inhibitors

KW - Histone Deacetylases/physiology

KW - Human T-lymphotropic virus 1/growth development

KW - Humans

KW - Jurkat Cells

KW - Paraparesis, Tropical Spastic/genetics/virology

KW - Proviruses/growth development

KW - Transcriptional Activation/physiology

KW - Transfection

KW - Valproic Acid/pharmacology

KW - Viral Load

U2 - 10.1182/blood-2007-04-085076

DO - 10.1182/blood-2007-04-085076

M3 - Article

VL - 110

JO - Blood

JF - Blood

SN - 0006-4971

IS - 10

ER -