Approximately 3% of all human Tlymphotropic 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. (Blood. 2010;116(19):3802-3808) IntroductionTen million to 20 million people are infected with human Tlymphotropic virus type 1 (HTLV-1) worldwide. This retrovirus is the etiologic agent of a malignant lymphoproliferative disease called adult T-cell leukemia/lymphoma (ATLL), 1,2 and of several inflammatory diseases, particularly of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). [3][4][5] Despite numerous clinical trials, no efficient treatment has yet been described for HAM/TSP patients. HAM/TSP is a neurodegenerative disease with major irreversible demyelination and loss of motor neurons from the pyramidal tract, 6-11 and the current treatments can only stabilize the clinical status of the patient. It is therefore necessary to develop therapies that can prevent the occurrence of this virus-associated neurodegenerative disease or at least block the evolution of the disease in the early stages of the pathogenesis.HTLV-1 infects a wide range of cells in vitro. However, in vivo, it is principally detected in CD4 ϩ T lymphocytes and, to a lesser extent, CD8 ϩ cells. [12][13][14][15][16] Importantly, there is an association between the HTLV-1 proviral load (PVL) and the clinical status of the persons. The PVL measured in the peripheral blood mononuclear cells (PBMCs) isolated from HAM/TSP patients is 5-to 20-fold higher than that of asymptomatic carriers (ACs). [17][18][19][20][21] Similarly, human leukocyte antigen genotypes associated with a low PVL are associated with a reduced risk of HAM/TSP. 22,23 It is therefore probable that the PVL in an AC will predict the risk of developing an HTLV-1-related disease. In ACs with a high PVL, diminishing the PVL may also prevent...

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