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
SN - 0006-4971
VL - 110
JO - Blood
JF - Blood
IS - 10
ER -