Depletion of latent HIV-1 infection in vivo: a proof-of-concept study
Depletion of latent HIV-1 infection in vivo: a proof-of-concept study
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DOI：
10.1016/s0140-6736(05)67098-5
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发表时间：
2005-08-13
期刊：
影响因子：
168.9
通讯作者：
Margolis, DM
中科院分区：
文献类型：
--
作者：
Lehrman, G;Hogue, IB;Margolis, DM
背景静止CD 4 + T细胞的持续感染阻止了HIV-1的根除。由于染色质重塑酶组蛋白去乙酰化酶1（HDAC 1）保持潜伏期的综合艾滋病病毒，我们测试的能力HDAC抑制剂丙戊酸消耗持续性，潜伏性感染的休息CD 4 + T cells.Procedures我们做了一个概念验证的研究，在四名志愿者感染艾滋病病毒和高活性抗逆转录病毒治疗（HAART）。在用皮下注射恩夫韦肽90 μ g，每日两次，持续4-6周加强HAART的效果以防止HIV传播后，我们在其治疗方案中加入口服丙戊酸500-750 mg，每日两次，持续3个月。我们量化的潜伏感染的静息CD 4 + T细胞之前和之后增强治疗静息CD 4 + T细胞体外activation.Findings后的有限稀释培养静息细胞感染的频率是稳定的恩夫韦肽和丙戊酸之前，但此后下降。这种下降在四名患者中的三名中是显著的（平均降低75%，范围68%至>84%）。患者有轻微的反应恩夫韦肽在注射部位，但在其他方面耐受治疗well.Interpretation与HDAC抑制剂和强化HAART联合治疗安全地加速清除HIV从静息的CD 4 + T细胞在体内，这表明一个新的和实用的方法来消除HIV感染在这个持久的水库。这一发现虽然不是决定性的，但表明新的方法将在未来治愈艾滋病毒。
Background Persistent infection in resting CD4+ T cells prevents eradication of HIV-1. Since the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV, we tested the ability of the HDAC inhibitor valproic acid to deplete persistent, latent infection in resting CD4+ T cells.Procedures We did a proof-of-concept study in four volunteers infected with HIV and on highly-active antiretroviral therapy (HAART). After intensifying the effect of HAART with subcutaneous enfuvirtide 90 mu g twice daily for 4-6 weeks to prevent the spread of HIV, we added oral valproic acid 500-750 mg twice daily to their treatment regimen for 3 months. We quantified latent infection of resting CD4+ T cells before and after augmented treatment by limiting-dilution culture of resting CD4+ T cells after ex-vivo activation.Findings The frequency of resting cell infection was stable before addition of enfuvirtide and valproic acid, but declined thereafter. This decline was significant in three of four patients (mean reduction 75%, range 68% to >84%). Patients had slight reactions to enfuvirtide at the injection site, but otherwise tolerated treatment well.Interpretation Combination therapy with an HDAC inhibitor and intensified HAART safely accelerates clearance of HIV from resting CD4+ T cells in vivo, suggesting a new and practical approach to eliminate HIV infection in this persistent reservoir. This finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future.