Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells.
Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells.
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DOI：
10.1016/j.ebiom.2017.07.019
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发表时间：
2017-09
期刊：
影响因子：
11.1
通讯作者：
Margolis DM
中科院分区：
文献类型：
--
作者：
Sung JA;Sholtis K;Kirchherr J;Kuruc JD;Gay CL;Nordstrom JL;Bollard CM;Archin NM;Margolis DM
潜伏性人类免疫缺陷病毒（HIV）感染的细胞是转录静止的，免疫系统无法清除。为了证明潜伏期逆转剂伏立诺他（VOR）诱导潜伏HIV储库中的脆弱性窗口，定义为触发病毒抗原产生的数量和持续时间足以识别和清除持续感染，我们开发了潜伏期清除试验（LCA）。LCA是一种定量病毒生长试验（QVOA），包括添加能够清除表达病毒抗原的细胞的免疫效应物。在这里，我们显示了在添加免疫效应子一段离散时间后，从VOR暴露的静息CD 4 T细胞中恢复有复制能力的病毒的减少。带回家的消息：VOR暴露导致细胞表面产生足够的病毒蛋白，在抗逆转录病毒治疗（ART）抑制的HIV感染个体中的潜伏库内产生脆弱性窗口，允许通过一系列效应机制清除潜伏感染的细胞。潜伏期清除测定可用于检测抗原产生和清除。伏立诺他在生理相关的体外暴露后诱导静息CD 4 T细胞中的HIV-1蛋白抗原。伏立诺他的潜伏期逆转允许通过多种效应机制清除。目前从体内根除HIV感染的努力包括一种多管齐下的策略，通过首先通过暴露于潜伏逆转剂诱导潜伏感染细胞产生HIV，然后清除现在可识别的感染细胞，从静息的CD 4 T细胞中清除潜伏的HIV-1储库。测量潜伏逆转剂诱导相关HIV产生的能力在技术上具有挑战性。使用潜伏期清除试验，我们检测了伏立诺他（一种临床研究中的潜伏期逆转剂）诱导细胞表面上可识别水平的HIV蛋白的能力，从而允许随后清除感染的细胞。
Latently human immunodeficiency virus (HIV)-infected cells are transcriptionally quiescent and invisible to clearance by the immune system. To demonstrate that the latency reversing agent vorinostat (VOR) induces a window of vulnerability in the latent HIV reservoir, defined as the triggering of viral antigen production sufficient in quantity and duration to allow for recognition and clearance of persisting infection, we developed a latency clearance assay (LCA). The LCA is a quantitative viral outgrowth assay (QVOA) that includes the addition of immune effectors capable of clearing cells expressing viral antigen. Here we show a reduction in the recovery of replication-competent virus from VOR exposed resting CD4 T cells following addition of immune effectors for a discrete period. Take home message: VOR exposure leads to sufficient production of viral protein on the cell surface, creating a window of vulnerability within this latent reservoir in antiretroviral therapy (ART)-suppressed HIV-infected individuals that allows the clearance of latently infected cells by an array of effector mechanisms. The Latency Clearance Assay can be employed to detect antigen production and clearance. Vorinostat induces HIV-1 protein antigen in resting CD4 T cells following a physiologically relevant in-vitro exposure. Latency reversal by vorinostat allows clearance by multiple effector mechanisms. Current efforts to eradicate HIV infection from the body include a multipronged strategy to purge the latent HIV-1 reservoir from resting CD4 T cells by first inducing HIV production from latently infected cells through exposure to latency reversing agents, followed by clearance of the now recognizable infected cells. Measuring a latency reversing agent's ability to induce relevant HIV production is technically challenging. Using a latency clearance assay, we have detected the ability of vorinostat, a latency reversing agent under clinical investigation, to induce recognizable levels of HIV protein on the cell surface allowing for subsequent clearance of infected cells.
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影响因子：
15.9
作者：
Liu, Michael K. P.;Hawkins, Natalie;Goonetilleke, Nilu
通讯作者：
Goonetilleke, Nilu
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
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影响因子：
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作者：
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