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

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

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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）：终身抗逆转录病毒疗法（ART）提出了强大的问题。因此，未来艾滋病毒研究的许多重要目标之一是开发能够消除艾滋病毒感染的临时疗法。少数长寿命CD4+ T细胞中静止的HIV感染的持久性目前是根除HIV感染的主要障碍。人的转录因子募集组蛋白脱乙酰基酶（HDACS）至HIV长末端重复启动子，介导凝结异染色质的形成，从而导致LTR表达和病毒产生的抑制。对HDAC抑制剂丙戊酸的研究未能测量ART患者中静息细胞感染的一致耗竭，但是这种作用在HDAC抑制剂的主要分子机制的下游远。我们已经证明了有效抑制剂在肿瘤学中使用的能力，Suberoylanilide羟氨基酸（Vorinostat，vor），I级HDAC的选择性，I级HDACS的选择性，诱导来自抗逆转录病毒抗逆转录病毒治疗的患者的静脉CD4+ T细胞中的细胞系中的HIV启动子表达和病毒。我们提出了一项主要研究证明，以测量有效的HDAC抑制剂在体内诱导持续性前病毒HIV表达的潜力。具体目标1：静止CD4-T细胞中可检测到的HIV RNA表达的频率将在体内暴露后增加：我们将在VOR剂量之前和之后比较HIV感染的患者在稳定的ART中静止的CD4+细胞中的HIV RNA表达。具体目标2：与ART结合使用ART对HIV-1感染的患者的VOR剂量有限，这是安全可容忍的：我们将表征VOR在HIV-1感染接受抗逆转录病毒疗法的成年患者中VOR的安全性，耐受性和副作用。尽管根除HIV感染的目的是遥远的目标，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，并为这种方法的早期人类测试建立新的范式。相关性（请参阅说明）：如果要从HIV感染的个体中消除病毒，则必须开发破坏静止CD4+ T淋巴细胞潜在感染的疗法。组蛋白脱乙酰基酶（HDAC）抑制剂破坏潜在的病毒后感染。我们将直接评估HDAC抑制剂对体内HIV潜伏期的影响。