Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors
Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors
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DOI：
10.1182/blood-2010-02-270751
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发表时间：
2010-11-11
期刊：
影响因子：
20.3
通讯作者：
Mahieux, Renaud
中科院分区：
文献类型：
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作者：
Afonso, Philippe V.;Mekaouche, Mourad;Mahieux, Renaud
大约3%的人类嗜T淋巴细胞病毒1型（HTLV-1）感染者将发展成中枢神经系统的致残性炎症性疾病，称为HTLV-1相关性脊髓病/热带痉挛性下肢轻瘫，目前还没有有效的治疗方法。由于前病毒载量（PVL）与携带者的临床状态之间存在相关性，因此认为减少PVL可以预防疾病的后期发生。我们在一系列自然感染猴嗜T淋巴细胞病毒1型（STLV-1）的狒狒中进行了一项丙戊酸盐（一种组蛋白脱乙酰酶抑制剂）和叠氮胸苷（一种逆转录酶抑制剂）联合治疗的研究，STLV-1的PVL与HTLV-1无症状携带者的PVL相当。我们表明，药物的组合引起了强烈的减少，PVL和防止短暂的上升，PVL后看到单独组蛋白脱乙酰酶治疗。然后，我们证明PVL下降与STLV-1特异性细胞毒性T细胞群的增加有关。我们得出结论，丙戊酸盐诱导病毒表达和叠氮胸苷预防病毒繁殖的联合治疗是降低体内PVL的安全有效方法。这种治疗可能有助于降低高PVL无症状携带者的HAM/TSP风险。（血。2010;116（19）：3802-3808）
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. (Blood. 2010;116(19):3802-3808)