A Pilot Trial of the effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection

伏立诺他和 AGS-004 对持续性 HIV-1 感染影响的初步试验

基本信息

批准号：
9022397
负责人：
DAVID M. MARGOLIS
金额：
$ 134.89万
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：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9022397
关键词：
Adverse effects Anti-Retroviral Agents Antigen Presentation Antiviral Agents Antiviral Therapy Autologous Autologous Dendritic Cells Biological Assay CD4 Positive T Lymphocytes CD40 Ligand CD8B1 gene Cell physiology Cells Data Dendritic Cell Vaccine Dendritic Cells Development Distant Dose Frequencies Future Genome Goals HIV HIV Antigens HIV Infections HIV-1 Health Histone Deacetylase Inhibitor Human Immune Immune response Immunity Immunization Immunotherapeutic agent In Vitro Infection Interruption Latent Virus Licensing Lymphocyte Measures Mediating Mississippi Participant Patients Phase Plasma Population RNA Regimen Research Research Infrastructure Rest Safety T-Lymphocyte Testing Therapeutic Vaccination Viral Viral Antigens Viremia Virus Virus Diseases Virus Replication Vorinostat Work antiretroviral therapy cost cytotoxic in vivo latent infection memory CD4 T lymphocyte novel oncology pilot trial purge therapeutic vaccine therapy development tool

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 populations of CD4+ T cells is currently a major obstacle to eradication of HIV infection. We will continue proof-of-concept studies attempting to directly and precisely measure the induction of proviral expression from the latently infected CD4+ cell reservoir, and the depletion of infection within that reservoir. We have demonstrated the ability of the HDAC inhibitor licensed for use in oncology, suberoylanilide hydroxamic acid (Vorinostat, VOR), selective for Class I HDACs, to induce HIV expression in the resting CD4+ T cells of antiretroviral-treated, aviremic HIV-infected patients in vivo. We have established the infrastructure and assays needed to document a repeated induction of resting CD4+ T cell-associated HIV RNA in vivo following repeated doses of VOR. Clearance of this small, latent reservoir upon relatively brief proviral induction may not be possible in the absence of a robust HIV-specific immune response. We have selected 2nd proof-of-concept tool, Argos AGS-004, an autologous dendritic cell vaccine that has demonstrated the ability to induce immunity in vivo as measured by a clinically apparent reduction in rebound viremia after ART interruption. AGS-004 consists of dendritic cells (DCs) co-electroporated with in vitro transcribed (IVT) ribonucleic acid (RNA) encoding specific autologous HIV antigens (Gag, Vpr, Rev, and Nef) to achieve antigen presentation, with CD40 ligand RNA, to enhance DC functionality. We have established the infrastructure and assays needed to document the induction of an appropriately durable antiviral immune response following AGS-004. We propose a proof-of-principal study to measure the potential of VOR and AGS-004 to deplete latent infection, following administration in a carefully validated combination: Specific Aim 1: The frequency of detectable HIV RNA expression within resting CD4+ T cells will increase after repeated VOR exposure in vivo Specific Aim 2: AGS-004 will induce an HIV-specific immune in HIV-infected participants with durable viral suppression on ART initiated, both prior to and following VOR administration. Specific Aim 3: A combination of serial AGS-004 vaccinations and

描述（由适用提供）：终身抗逆转录病毒疗法（ART）提出了巨大的问题。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。 CD4+ T细胞种群中静止的HIV感染的持续性目前是HIV感染辐射的主要障碍。我们将继续概念验证研究，试图直接和精确地衡量潜在感染的CD4+细胞储层的临时表达以及该储层中感染的部署。我们已经证明了HDAC抑制剂在肿瘤学中使用的能力，Suberoylanilide羟氨酸（Vorinostat，vor，vor），I级HDACs的选择性，在抗逆转录病毒治疗，Avirememicted，Avirememicted，Avirememicted，Avirememicted，Avirememicted，Avirememported，Avirememaliagemented，Avirememaliagected，Avirememporemected hiv hiv感染的患者中诱导HIV表达。我们已经建立了在重复剂量的VOR后重复引入体内静止CD4+ T细胞相关的HIV RNA所需的基础设施和暗示。在没有强大的HIV特异性免疫反应的情况下，可能无法在相对短暂的临时诱导时清除这种小的潜在储层。我们选择了第二概念验证工具Argos AGS-004，这是一种自体树突状细胞疫苗，该疫苗证明了在ART中断后临床上明显降低反弹病毒血症的临床明显降低，从而证明了在体内诱导免疫学的能力。 AGS-004由与体外转录（IVT）缎带共同构图的树突状细胞（DCS）组成编码特定自体HIV抗原（GAG，VPR，REV和NEF）的酸（RNA），用CD40配体RNA实现抗原呈递，以增强直流功能。我们已经建立了在AGS-004之后记录适当耐用的抗病毒免疫反应所需的基础设施和分析。 We propose a proof-of-principal study to measure the potential of VOR and AGS-004 to replicate latent infection, following administration in a carefully validated combination: Specific Aim 1: The frequency of detectable HIV RNA expression within resting CD4+ T cells will increase after repeated VOR exposure in vivo Specific Aim 2: AGS-004 will induce an HIV-specific immunology in HIV-infected participants with durable viral suppression on ART在VOR给药之前和之后启动。特定目的3：串行AGS-004疫苗接种和结合