Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors.
Approximately 3% of all human T-lymphotropic virus type 1 (HTLV-1)-infected persons will develop a disabling inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis, against which there is currently no efficient treatment. As correlation exists between the proviral load (PVL) and the clinical status of the carrier, it is thought that diminishing the PVL could prevent later occurrence of the disease. We have conducted a study combining valproate, an inhibitor of histone deacetylases, and azidothymidine, an inhibitor of reverse transcriptase, in a series of baboons naturally infected with simian T-lymphotropic virus type 1 (STLV-1), whose PVL was equivalent to that of HTLV-1 asymptomatic carriers. We show that the combination of drugs caused a strong decrease in the PVL and prevented the transient rise in PVL that is seen after treatment with histone deacetylases alone. We then demonstrate that the PVL decline was associated with an increase in the STLV-1-specific cytotoxic T-cell population. We conclude that combined treatment with valproate to induce viral expression and azidothymidine to prevent viral propagation is a safe and effective means to decrease PVL in vivo. Such treatments may be useful to reduce the risk of HAM/TSP in asymptomatic carriers with a high PVL.
Afonso
Philippe V
PV
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Centre National de la Recherche Scientifique (CNRS) URA 3015, Institut Pasteur, Paris, France.
Mekaouche
Mourad
M
Mortreux
Franck
F
Toulza
Frédéric
F
Moriceau
Antoine
A
Wattel
Eric
E
Gessain
Antoine
A
Bangham
Charles R M
CR
Dubreuil
Guy
G
Plumelle
Yves
Y
Hermine
Olivier
O
Estaquier
Jérome
J
Mahieux
Renaud
R
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D006800:Deltaretrovirus Infections / Q000188:drug therapy / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D015490:HTLV-I Infections / Q000188:drug therapy / Q000821:virology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008992:Monkey Diseases / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D010215:Papio; D015493:Paraparesis, Tropical Spastic / Q000188:drug therapy / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D015303:Simian T-lymphotropic virus 1; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D014635:Valproic Acid / Q000008:administration & dosage; D019562:Viral Load / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage
D000998:Antiviral Agents; D056572:Histone Deacetylase Inhibitors; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D014635:Valproic Acid