BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication

相信：从床到床增强淋巴细胞输注可实现病毒根除

• 批准号: 9768885
• 负责人: R. Brad Jones
• 金额: $ 555.55万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768885
• 关键词: Adherence; Adult; Anatomy; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Applications Grants; B-Lymphocytes; BLR1 gene; Basic Science; Beds; Belief; Berlin; Cell physiology; Cells; Child; Clinical; Clinical Research; Combined Modality Therapy; Communities; Comorbidity; Cytotoxic T-Lymphocytes; Drug toxicity; Effector Cell; Engineering; Ensure; Epidemic; Epitopes; Future; Goals; HIV; HIV Infections; Histone Deacetylase; Home environment; Homing; Human; Immune; Immune system; Immunity; Immunotherapeutic agent; In Vitro; Individual; Infusion procedures; Interleukin-15; Intervention; Latent Virus; Lead; Leadership; Life; Life Expectancy; Lymphocyte; Lymphoid Tissue; Mediating; Mississippi; Modality; Molecular; Mus; NK Cell Activation; Natural Killer Cells; Nature; Patients; Persons; Phase I Clinical Trials; Positioning Attribute; Pre-Clinical Model; Recording of previous events; Research; Research Personnel; SIV; Shock; Site; T-Lymphocyte; Testing; Therapeutic; Translations; Vaccination; Vaccine Therapy; Viral; Viral reservoir; Virus; Virus Latency; Woman; antiretroviral therapy; autologous lymphocytes; collaboratory; design; drug resistant virus; engineered NK cell; engineered T cells; exhaust; experimental study; improved; in vivo; inhibitor/antagonist; insight; minority investigator; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel strategies; pediatric human immunodeficiency virus infection; pre-clinical; response; small molecule inhibitor

Project Abstract This new grant application is in response to the “Martin Delaney Collaboratories for HIV Cure Research (UM1)” RFA. We call our application “BELIEVE”, short for “Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication”. One individual, known as the “Berlin patient”, is considered to be cured of HIV, with no evidence for active replication competent virus in the absence of antiretroviral (ARV) therapy. The “Mississippi” baby initially appeared to be another cure, but virus re-emerged a couple of years after ARV cessation. ARV therapy prolongs life, but a life expectancy gap shows patients on viral suppressive therapies live a shorter life, and have more co-morbidities. To help end the epidemic, an HIV cure is needed. Current “shock and kill” strategies are limited in harnessing the power of immunity in seeking and removing latent cells. Augmentation of immunity could be performed through vaccination, although therapeutic vaccination in HIV infection has had limited efficacy to date. In addition, immune effectors in HIV infected persons are not fully recovered with ARV treatment. There are at least three mechanisms which lead to the inability of the immune system to remove virus completely: (1) a weakened and exhausted cytotoxic T- lymphocyte (CTL) response from which epitope escape has occurred, (2) over activated but under performing Natural Killer cells, and (3) inability of effector cells to reach the right sites where latent virus reside. Our proposal has objectives, broadly defined, that are aimed at understanding how to enhance the killing ability of HIV specific cytotoxic T lymphocytes, to augment NK cell functions, and to harness T-cell, NK cell and antibody mediated effectors in the context of adult and pediatric HIV infections. First, we will immediately initiate a pilot clinical study with our most promising combination of T-cell infusion and latency-reversing agents. We will compare this combination to enhanced natural and engineered T-cells to eradicate HIV reservoirs (in vitro, in mice, in non-human primates, and in additional human clinical studies), in association with novel HIV Nef small molecule inhibitors. Second, we will develop and test enhanced Natural Killer cells with or without broadly neutralizing antibodies (in mice, in non human primates, and in humans). Third, we will target sites of viral latency which CTL cannot reach, by targeting CTL to home to reservoir sites. We have gathered a group of accomplished investigators, with strong collaborative histories, along with community advisors. Around 40% of the scientific leadership positions are women, and there are representatives of early stage and minority investigators, and two corporate partners, all driven by the belief that a cure will depend on enhancing anti-HIV immunity in association with latency reversal.

项目摘要 这项新的赠款应用程序是对“艾滋病毒治疗研究（UM1）的马丁·德莱尼合作者”的回应。 RFA。我们称我们的应用程序为“相信”，缩写为“卧床床增强的淋巴细胞输注” 工程师消除病毒。一个被称为“柏林患者”的人被认为是用艾滋病毒治愈的 在没有抗逆转录病毒（ARV）治疗的情况下，没有证据表明主动复制能干病毒。这 “密西西比”婴儿最初似乎是另一种治疗方法，但病毒在ARV后几年重新出现 停止。 ARV疗法延长了寿命，但预期寿命差距显示患者接受病毒抑制疗法 过着较短的寿命，并拥有更多的合并症。为了帮助结束流行病，需要治愈艾滋病毒。 当前的“震惊和杀戮”策略在利用免疫力寻求和去除方面受到限制 潜在细胞。尽管治疗 迄今为止，艾滋病毒感染中的疫苗接种效率有限。另外，HIV感染中的免疫作用 ARV治疗未完全康复。至少有三种机制导致 免疫系统无法完全清除病毒：（1）弱化和耗尽的细胞毒性T- 淋巴细胞（CTL）的反应发生了表位逃脱，（2）激活但在执行下 天然杀伤细胞和（3）效应细胞无法到达潜在病毒居住的正确部位。 我们的建议具有广义定义的目标，旨在了解如何增强杀戮能力 HIV特异性细胞毒性T淋巴细胞，增强NK细胞功能，并利用T细胞，NK细胞和 抗体介导的作用在成人和小儿艾滋病毒感染的背景下。首先，我们会立即 通过我们最有希望的T细胞输注和逆转延迟的结合来启动一项试点临床研究 代理商。我们将比较这种组合以增强自然和工程的T细胞与放射性艾滋病毒 水库（在体外，在小鼠，非人类隐私和其他人类临床研究中） 新型HIV NEF小分子抑制剂。其次，我们将开发和测试增强的自然杀手细胞 有或没有广泛中和抗体（在小鼠，非人类灵长类动物和人类中）。第三，我们会的 CTL无法达到病毒潜伏期的目标位点，将CTL靶向在家中的储层站点。 我们已经聚集了一群成熟的调查员，拥有较强的合作历史，以及 社区顾问。大约40％的科学领导职务是女性，并且有 代表早期阶段和少数群体调查员以及两个公司合作伙伴，都源于信念 治愈将取决于增强与潜伏期逆转的抗HIV免疫。