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（由申请人提供）：终身抗逆转录病毒治疗（ART）提出了严峻的问题，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控制疗法。 CD4+ T 细胞目前是根除 HIV 感染的主要障碍，我们将继续进行概念验证研究，尝试直接、精确地测量潜伏感染 CD4+ 诱导原病毒表达的情况。我们已经证明了用于肿瘤学的 HDAC 抑制剂辛二酰苯胺异羟肟酸（Vorinostat，VOR），对 I 类 HDAC 具有选择性，能够诱导静息 CD4+ 中的 HIV 表达。接受抗逆转录病毒治疗的无病毒血症 HIV 感染患者体内的 T 细胞我们已经建立了记录静息 CD4+ T 细胞相关 HIV 重复诱导所需的基础设施和测定方法。如果没有强大的 HIV 特异性免疫反应，重复剂量 VOR 后体内的 RNA 可能无法在相对短暂的原病毒诱导下清除。我们选择了第二个概念验证工具 Argos AGS。 -004，一种自体树突状细胞疫苗，通过 ART 中断后临床上明显的病毒血症反弹减少来衡量，该疫苗已证明具有诱导体内免疫的能力，该疫苗由树突状细胞组成。 (DC) 与体外转录 (IVT) 核糖核酸共电穿孔编码特定自体 HIV 抗原（Gag、Vpr、Rev 和 Nef）的酸 (RNA) 与 CD40 配体 RNA 一起实现适当的抗原呈递，以增强 DC 功能。我们已经建立了记录持久诱导的基础设施和测定方法。我们提出了一项原理验证研究，以测量 VOR 和 AGS-004 在经过仔细验证的组合后消除潜伏感染的潜力：特异性目标 1：在体内重复 VOR 暴露后，静息 CD4+ T 细胞内可检测到的 HIV RNA 表达频率将会增加具体目标 2：AGS-004 将在 HIV 感染者中诱导 HIV 特异性免疫，并在 ART 启动时产生持久的病毒抑制，在 VOR 给药之前和之后具体目标 3：连续 AGS-004 疫苗接种和