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

 描述(由申请人提供)：终生抗逆转录病毒疗法(ART)带来了巨大的问题。因此，未来艾滋病毒研究的许多重要目标之一是开发能够根除艾滋病毒感染的临时控制疗法。目前，在CD4+T细胞群体中持续存在静止的艾滋病毒感染是根除艾滋病毒感染的主要障碍。我们将继续进行概念验证研究，试图直接和准确地测量潜伏感染的CD4+细胞库中前病毒表达的诱导，以及该库中感染的耗竭。我们已经证明了被许可用于肿瘤学的HDAC抑制剂Suberoylanilide羟肟酸(Vorinostat，VOR)对I类HDAC具有选择性，能够在体内诱导抗逆转录病毒治疗的无抵抗HIV感染患者的静止CD4+T细胞中HIV的表达。我们已经建立了所需的基础设施和检测方法，以证明重复剂量的VOR在体内重复诱导与静止的CD4+T细胞相关的HIV RNA。在没有强大的HIV特异性免疫反应的情况下，在相对短暂的前病毒诱导后清除这个小的、潜在的宿主可能是不可能的。我们选择了第二个概念验证工具Argos AGS-004，这是一种自体树突状细胞疫苗，已经证明了在体内诱导免疫的能力，通过ART中断后临床上反弹病毒血症的明显减少来衡量。AGS-004由共电穿孔的树突状细胞(DC)和体外转录(IVT)核糖核组成 编码特定的自体HIV抗原(GAG、VPR、REV和Nef)的酸(RNA)，以实现抗原递呈，与CD40配体RNA一起，以增强DC功能。我们已经建立了所需的基础设施和检测方法，以证明在AGS-004之后诱导适当持久的抗病毒免疫反应。我们建议进行一项主证性研究，以衡量VOR和AGS-004在仔细验证的联合给药后消除潜伏感染的潜力：特定目标1：在体内重复暴露VOR后，静止的CD4+T细胞中可检测到的HIV RNA表达的频率将增加。特定目标2：AGS-004将在HIV感染参与者中诱导HIV特异性免疫，在VOR给药之前和之后对ART启动持久的病毒抑制。具体目标3：AGS-004系列疫苗和

 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