Simultaneous latent HIV reactivation and cytokine gene suppression

同时潜伏的 HIV 重新激活和细胞因子基因抑制

• 批准号: 8701801
• 负责人: MONTY A MONTANO
• 金额: $ 62.34万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701801
• 关键词: Address; Affect; Anti-Retroviral Agents; Automobile Driving; Bromodomain; CD4 Positive T Lymphocytes; Cell Line; Chronic; Comorbidity; Cytokine Gene; Cytokine Suppression; Drug resistance; Drug toxicity; Endotoxins; Gene Expression; Genes; Genetic Transcription; HIV; HIV-1; Highly Active Antiretroviral Therapy; Histone Deacetylase Inhibitor; In Vitro; Individual; Infection; Inflammation; Inflammatory; Malignant Neoplasms; Mitogens; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Pharmaceutical Preparations; Pilot Projects; Positive Transcriptional Elongation Factor B; Production; Proviruses; Regimen; Rest; Risk; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transcriptional Elongation Factors; Viral; Vorinostat; antiretroviral therapy; compliance behavior; cytokine; factor EF-P; novel; novel strategies; p65; pandemic disease; programs; promoter; purge; small molecule; success; tat Protein

DESCRIPTION (provided by applicant): The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. Prior attempts at purging viral reservoirs have included T cell mitogens or histone deacetylase inhibitors (HDACIs) with limited success in reducing the viral reservoir, underscoring the need for additional approaches that promote viral reactivation. This proposal is motivated by our recent discovery [1] that a small molecule, JQ1, initially identified as a potent bromodomain-4 (Brd4) antagonist and cancer suppressor, potently upregulates latent and induced HIV proviral expression in cell lines and primary CD4+ T cells. In addition, JQ1 suppresses systemic inflammatory cytokine production in mice acutely exposed to endotoxin and suppresses T cell activation genes in primary CD4+ T cells. JQ1 therefore represents a novel compound with desirable features and translational utility. Our overall hypothesis is that JQ1 promotes viral reactivation and suppresses NF-kB driven gene expression by modulating Brd4 activity. As a result of interfering with Brd4 activity at the HIV promoter, JQ1 may increase access of the viral Tat protein to the host positive transcriptional elongation factor (P-TEFb). At cytokine gene promoters, we hypothesize that JQ1 interferes with acetylated p65/RelA interaction with Brd4 resulting in declines in NF- B driven cytokine gene expression, but not NFAT driven gene expression. To address our hypothesis, we propose a translational program to characterize this compound's effect on HIV proviral reactivation and on cytokine gene expression in latent T cell lines, an in vitro latency model for primary T cells and in resting CD4+ T cells from infected individuals receiving effective ART.

描述（由申请人提供）：潜伏 HIV-1 的持续存在仍然是根除感染的治疗工作中的一个主要挑战。先前尝试清除病毒库 包括 T 细胞有丝分裂原或组蛋白脱乙酰酶抑制剂 (HDACIs) 在减少病毒储存方面取得的成功有限，这强调需要采取其他方法来促进病毒重新激活。这一提议的动机是我们最近的发现 [1]，一种小分子 JQ1 最初被鉴定为有效的 bromodomain-4 (Brd4) 拮抗剂和癌症抑制剂，可有效上调细胞系和原代 CD4+ T 细胞中潜在的和诱导的 HIV 前病毒表达。此外，JQ1 还能抑制急性暴露于内毒素的小鼠体内全身炎症细胞因子的产生，并抑制原代 CD4+ T 细胞中的 T 细胞激活基因。因此，JQ1 代表了一种具有理想特征和转化效用的新型化合物。我们的总体假设是 JQ1 通过调节 Brd4 活性促进病毒再激活并抑制 NF-kB 驱动的基因表达。由于干扰 HIV 启动子处的 Brd4 活性，JQ1 可能会增加病毒 Tat 蛋白与宿主正转录延伸因子 (P-TEFb) 的接触。在细胞因子基因启动子处，我们假设 JQ1 干扰乙酰化 p65/RelA 与 Brd4 的相互作用，导致 NF-B 驱动的细胞因子基因表达下降，但不影响 NFAT 驱动的基因表达。为了解决我们的假设，我们提出了一个转化程序来表征该化合物对 HIV 原病毒再激活和潜伏 T 细胞系中细胞因子基因表达的影响，这是一种原代 T 细胞的体外潜伏模型， 接受有效 ART 的感染者的静息 CD4+ T 细胞。