A Pilot Clinical Trial for HIV-1 Eradication

根除 HIV-1 的试点临床试验

基本信息

批准号：
9197496
负责人：
Daniel R. Kuritzkes
金额：
$ 213.99万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2015-02-15 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197496
关键词：
Anti-Retroviral Agents Biological Assay CD4 Positive T Lymphocytes CD8B1 gene Cells Cessation of life Charge Chronic Clinical Clinical Pharmacology Clinical Trials Collaborations Combined Modality Therapy Conduct Clinical Trials Cytometry DNA Data Dendritic Cells Detection Development Disease remission Effector Cell Frequencies Gene Expression Gene Expression Profiling Genes Genetic Transcription Goals HIV HIV-1 Histone Deacetylase Inhibitor Human Human body Immune Immune response Immunology Infection Interferon-alpha Interferons Interruption Intervention Kinetics Lead Life Mass Spectrum Analysis Measures Mediating Monitor Myelogenous Natural Immunity Natural Killer Cells Outcome Participant Patient Care Patients Pattern Pharmaceutical Preparations Pharmacologic Substance Plasma Protocols documentation RNA Randomized Research Personnel Safety Statistical Data Interpretation T-Lymphocyte T-Lymphocyte Subsets Testing Time Treatment Protocols Viral Viral reservoir Work antiretroviral therapy base design immune activation in vivo interdisciplinary collaboration memory CD4 T lymphocyte novel novel strategies patient subsets public health relevance virology

项目摘要

DESCRIPTION (provided by applicant): Although HIV-1 replication can be effectively suppressed with currently existing antiretroviral drugs, infection with HIV-1 remains incurable. This is primarily related to the ability of HIV-1 to establish a latent reservoir of HIV-1-infected CD4 T cells that is unresponsive to currently available antiretroviral agents. Pharmacological reactivation of active HIV-1 gene expression in latently infected cells can result in cellular deat due to cytopathic effects or immune mediated clearance, and represents one of the most promising and most clinically advanced strategies to target latently infected cells. Results from prior pilot clinical trials, conducted in collaboration with the applicants, demonstrate that the potent histone deacetylase inhibitor (HDACi) panobinostat is effective in reversing HIV-1 latency and transiently increasing plasma HIV-1 RNA in vivo. In addition, this work indicated that viral reactivation with panobinostat resulted in a 3-4 fold reduction of CD4 T cell-associated HIV-1 DNA in a subset of patients, and that this decrease was associated with delayed viral rebound kinetics during an analytical treatment interruption. Interestingly, a detailed analysis of immune parameters revealed that decrease of HIV-1 DNA during panobinostat treatment was unrelated to the magnitude or breadth of HIV-1-specific CD8 T cells, but instead strongly correlated to the proportion of activated innate effector cells, such as NK cells and plasmacytoid dendritic cells. Together, these data suggest that HDACi can be used effectively as latency-reversing agents, and that innate effector cell immune responses are critical for reducing the reservoir of latently infected cells when viral reactivation is pharmacologically induced. This project sets out to integrate these observations into a conceptually novel HIV- 1 eradication strategy that is based on treatment with panobinostat as a latency-reversing agent in combination with pegylated IFNa-2a as an innate immune activator. We hypothesize that the concomitant use of both agents leads to innate immunity-dependent elimination of latently infected cells in which viral reactivation is pharmacologically induced. Specific aim (SA) 1 will focus on conducting a pilot clinical trial in which n=30 ART-treated HIV-1 patients will be randomized 2:1 to treatment with panobinostat and PEG-IFNa-2a during four one-week cycles, each of them separated by a three-week observation period, or to four cycles of treatment with panobinostat alone. In SA 2, we will investigate how the combined treatment regimen influences CD4 T cell-associated HIV-1 RNA, plasma RNA, HIV-1 DNA levels and the frequency of cells harboring replication-competent HIV-1. SA 3 is designed to comprehensively analyze immune effects associated with decreases in viral reservoir size, using a novel high-throughput mass spectrometry approach in combination with gene expression profiling and functional assays. This study represents an interdisciplinary collaboration of investigators with complementary expertise in HIV-1 virology, immunology, pharmacology and clinical patient care, and will be highly informative for the development of clinical strategies aiming at HIV-1 eradication.

描述（由适用提供）：尽管当前现有的抗逆转录病毒药物可以有效地抑制HIV-1复制，但HIV-1感染仍然无法治愈。这主要与HIV-1建立HIV-1感染的潜在储藏的能力有关 CD4 T细胞对当前可用的抗逆转录病毒药物无反应。由于细胞病变作用或免疫介导的清除率，在潜在感染细胞中活跃的HIV-1基因表达的药理重新激活可能导致细胞多，并且代表了针对潜在感染细胞的最有前途，最先进的策略之一。与申请人合作进行的先前试验临床试验的结果表明，有效的组蛋白脱乙酰基酶抑制剂（HDACI）Panobinostat可有效逆转HIV-1潜伏期，并在体内瞬时增加血浆HIV-1 RNA。此外，这项工作表明，在一部分患者中，带有链球托运的病毒重新激活导致与CD4 T细胞相关的HIV-1 DNA的3-4倍降低，并且在分析治疗过程中，这种降低与延迟的病毒反弹动力学有关。有趣的是，对免疫反应的详细分析。参数表明，在链球托管治疗期间HIV-1 DNA的降低与HIV-1特异性CD8 T细胞的大小或广度无关，但与活化的先天效应细胞（例如NK细胞和质子囊藻型树突状细胞）的比例密切相关。总之，这些数据表明，HDACI可以有效地用作延迟逆转剂，而先天效应细胞免疫反应对于在药理诱导病毒重新激活时降低潜在感染细胞的储层至关重要。该项目旨在将这些观察结果整合到概念性的新颖的HIV-1根除策略中，该策略基于Panobinostat作为一种延迟逆转剂的治疗，并将其与Pegypated IFNA-2A结合在一起，作为先天性免疫反应剂。我们假设两种药物的伴随使用都会导致先天免疫依赖性消除潜在感染的细胞，在该细胞中，病毒反应活化剂是药理诱导的。具体目的（SA）1将集中于进行一项试验临床试验，在该试验中，n = 30例ART治疗的HIV-1患者将在四个星期的周期中随机分组2：1，用panobinostat和peg-ifna-2a进行治疗，每个周期都以三周的观察期分隔，或者单独使用panibinostat的四个周期。在SA 2中，我们将研究联合治疗方案如何影响CD4 T细胞相关的HIV-1 RNA，等离子体RNA，HIV-1 DNA水平以及具有复制功能相比HIV-1的细胞的频率。 SA 3旨在全面地分析与病毒鉴定大小的恶化相关的免疫作用，并使用一种新型的高通量质谱法与基因表达分析和功能分析结合使用。这项研究代表了研究人员在HIV-1病毒学，免疫学，药理学和临床患者护理方面具有完整专业知识的研究人员的跨学科合作，并且对于开发旨在HIV-1放射分配的临床策略的信息非常有用。