Lehrman Ginger, Hogue Ian B, Palmer Sarah, Jennings Cheryl, Spina Celsa A, Wiegand Ann, Landay Alan L, Coombs Robert W, Richman Douglas D, Mellors John W, Coffin John M, Bosch Ronald J, Margolis David M
University of Texas Southwestern Medical Center at Dallas, Department of Medicine, Division of Infectious Diseases, 5323 Harry Hines Boulevard, Dallas, TX 753901, USA.
Lancet. 2005;366(9485):549-55. doi: 10.1016/S0140-6736(05)67098-5.
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.
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 mug 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.
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.
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.
静息CD4+ T细胞中的持续性感染阻碍了HIV-1的根除。由于染色质重塑酶组蛋白去乙酰化酶1（HDAC1）维持整合型HIV的潜伏状态，我们测试了HDAC抑制剂丙戊酸清除静息CD4+ T细胞中持续性潜伏感染的能力。
我们对4名感染HIV且正在接受高效抗逆转录病毒治疗（HAART）的志愿者进行了一项概念验证研究。在用皮下注射恩夫韦肽每日两次、每次90微克，持续4 - 6周以增强HAART效果从而防止HIV传播之后，我们在其治疗方案中添加每日两次、每次500 - 750毫克的口服丙戊酸，持续3个月。我们通过对体外激活后的静息CD4+ T细胞进行有限稀释培养，对强化治疗前后静息CD4+ T细胞的潜伏感染进行定量。
在添加恩夫韦肽和丙戊酸之前，静息细胞感染频率稳定，但此后下降。4名患者中有3名出现了显著下降（平均降低75%，范围为68%至>84%）。患者在注射部位对恩夫韦肽有轻微反应，但在其他方面对治疗耐受性良好。
HDAC抑制剂与强化HAART联合治疗可在体内安全加速HIV从静息CD4+ T细胞中的清除，这表明一种新的实用方法可消除该持续性储存库中的HIV感染。这一发现虽不确凿，但表明新方法将使未来治愈HIV成为可能。
