A Phase II/II Investigation of the Effect of Vorinostat (VOR) in HIV Infection

伏立诺他 (VOR) 对 HIV 感染影响的 II/II 期研究

基本信息

批准号：
8144516
负责人：
DAVID M. MARGOLIS
金额：
$ 56.55万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144516
关键词：
Acetylation Adult Adverse effects Anti-Retroviral Agents Biological Models CD4 Positive T Lymphocytes Cell Line Cell surface Cells Chromatin Clinical Trials Development Distant Dose Dose-Limiting Emodin Enrollment Environment Evaluation Event Exposure to Frequencies Future Gene Expression Genetic Transcription Genome Goals HIV HIV Infections HIV Long Terminal Repeat HIV-1 Heterochromatin Histone Deacetylase Inhibitor Histones Human Immune system In Vitro Individual Infection Instruction Interphase Cell Investigation Laboratories Licensing Life Long Terminal Repeats Malignant Neoplasms Measures Mediating Molecular Mutagens National Institute of Allergy and Infectious Disease Outcome Study Patients Pharmaceutical Preparations Phase Pilot Projects Population Production Recruitment Activity Repression Research Rest Risk Safety Screening procedure Testing Therapeutic Translating Up-Regulation Valproic Acid Viral Viremia Virus Vorinostat antiretroviral therapy clinical effect combinatorial drug candidate in vivo inhibitor/antagonist latent infection oncology preclinical study promoter purge transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): Lifelong antiretroviral therapy (ART) presents formidable problems. Therefore, among the many important goals for future HIV research is the development of temporally contained therapies capable of eradicating HIV infection. The persistence of quiescent HIV infection within a small population of long-lived CD4+ T cells is currently a major obstacle to the eradication of HIV infection. Human transcription factors recruit histone deacetylases (HDACs) to the HIV long terminal repeat promoter, mediating the formation of condensed heterochromatin, resulting in repression of LTR expression and viral production. Studies of the weak HDAC inhibitor valproic acid failed to measure a consistent depletion of resting cell infection in patients on ART, but this effect is far downstream of the primary molecular mechanism of HDAC inhibitors. We have demonstrated the ability of the potent inhibitor licensed for use in oncology, suberoylanilide hydroxamic acid (Vorinostat, VOR), selective for Class I HDACs, to induce HIV promoter expression in cell lines and virus production from the resting CD4+ T cells of antiretroviral-treated, aviremic HIV-infected patients. We propose a proof-of-principal study to measure the potential of potent HDAC inhibitors to induce the expression of persistent proviral HIV in vivo. Specific Aim 1: The frequency of detectable HIV RNA expression within resting CD4-- T cells will increase after VOR exposure in vivo: We will compare HIV RNA expression within resting CD4+ cells in HIV-infected patients on stable ART before and after VOR dosing. Specific Aim 2: Limited dosing of VOR in combination with ART to patients with HIV-1 infection will be safe and tolerable: We will characterize the safety, tolerability and spectrum of side effects of VOR in adult patients with HIV-1 infection receiving combination antiretroviral therapy. Although the goal of eradication of HIV infection is a distant one, this project may validate the ability of HDAC inhibitors to contribute to the purging of persistent infection and establish a new paradigm for early phase human testing of such approaches. RELEVANCE (See instructions): If eradication of virus from HIV-infected individuals is ever to be achieved, therapies that disrupt latent infection of resting CD4+ T-lymphocytes must be developed. Histone deacetylase (HDAC) inhibitors disrupt latent proviral infection ex vivo. We will directly assess the effect of HDAC inhibitors on HIV latency in vivo.

描述（由申请人提供）：终生抗逆转录病毒治疗（ART）存在严峻的问题。因此，未来艾滋病毒研究的许多重要目标之一是开发能够根除艾滋病毒感染的暂时抑制疗法。目前，在少数长寿命 CD4+ T 细胞中，静态 HIV 感染的持续存在是根除 HIV 感染的主要障碍。人类转录因子将组蛋白脱乙酰酶 (HDAC) 募集至 HIV 长末端重复启动子，介导浓缩异染色质的形成，从而抑制 LTR 表达和病毒产生。对弱 HDAC 抑制剂丙戊酸的研究未能测量 ART 患者静息细胞感染的持续消耗，但这种作用远远低于 HDAC 抑制剂主要分子机制。我们已经证明了被许可用于肿瘤学的强效抑制剂辛二酰苯胺异羟肟酸（Vorinostat，VOR）对 I 类 HDAC 具有选择性，能够诱导细胞系中 HIV 启动子的表达以及抗逆转录病毒药物的静息 CD4+ T 细胞产生病毒的能力。接受治疗的无病毒血症艾滋病毒感染者。我们提出了一项原理验证研究，以测量有效的 HDAC 抑制剂在体内诱导持久性前病毒 HIV 表达的潜力。具体目标 1：体内 VOR 暴露后，静息 CD4-T 细胞内可检测到的 HIV RNA 表达频率将会增加：我们将比较接受稳定 ART 治疗的 HIV 感染患者在 VOR 给药前后静息 CD4+ 细胞内的 HIV RNA 表达。具体目标 2：对 HIV-1 感染患者进行有限剂量的 VOR 与 ART 联合治疗将是安全且可耐受的：我们将描述接受联合抗逆转录病毒治疗的成年 HIV-1 感染患者中 VOR 的安全性、耐受性和副作用谱治疗。尽管根除 HIV 感染的目标还很遥远，但该项目可能会验证 HDAC 抑制剂有助于清除持续感染的能力，并为此类方法的早期人体测试建立新的范例。相关性（参见说明）：如果要从 HIV 感染者身上根除病毒，就必须开发出破坏静息 CD4+ T 淋巴细胞潜伏感染的疗法。组蛋白脱乙酰酶 (HDAC) 抑制剂可破坏体外潜伏的前病毒感染。我们将直接评估 HDAC 抑制剂对体内 HIV 潜伏期的影响。