HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat
HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat
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DOI：
10.1093/infdis/jiu155
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发表时间：
2014-09-01
影响因子：
6.4
通讯作者：
Margolis, David M.
中科院分区：
文献类型：
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作者：
Archin, Nancy M.;Bateson, Rosalie;Margolis, David M.
背景。组蛋白去乙酰化酶抑制剂伏立诺他（VOR）单剂量可上调接受治疗的无病毒血症的人类免疫缺陷病毒（HIV）阳性参与者的静息CD4(+) T细胞内的HIV RNA表达。据我们所知，多次使用VOR反复破坏潜伏性的能力尚未直接测定。
方法。5名在单剂量VOR后静息CD4(+) T细胞相关HIV RNA（rc - RNA）增加的参与者同意在周一至周三每日接受VOR，共8个周期。检测VOR血清水平、外周血单个核细胞组蛋白乙酰化、血浆HIV RNA单拷贝检测、rc - RNA、细胞内总HIV DNA以及来自静息CD4(+) T细胞的定量病毒生长检测。
结果。VOR耐受性良好，暴露量在预期参数范围内。然而，在第11剂（第4周期第2剂）或第22剂（第8周期第2剂）后测量的rc - RNA仅在5名参与者中的3名显著增加，并且与单剂量后相比，rc - RNA增加的幅度大幅降低。组蛋白乙酰化的变化减弱。定量病毒生长和其他检测的结果未改变。
结论。尽管HIV潜伏性被初始VOR剂量破坏，但在本方案中后续剂量的作用大幅降低。我们假设VOR的整体作用导致一个≥24小时的不应期。VOR给药的最佳方案仍有待确定。
Background. A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.Methods. Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed.Results. VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged.Conclusions. Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of >= 24 hours. The optimal schedule for VOR administration is still to be defined.