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: 9315726
• 负责人: DOUGLAS F NIXON
• 金额: $ 533.46万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-14 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315726
• 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; Viral; Viral reservoir; Virus; Virus Latency; Woman; antibody engineering; antiretroviral therapy; autologous lymphocytes; collaboratory; design; drug resistant virus; exhaust; experimental study; improved; in vivo; inhibitor/antagonist; insight; killings; 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 这项新的拨款申请是为了响应“马丁·德莱尼艾滋病毒治疗研究合作实验室 (UM1)” 射频消融。我们将我们的应用程序称为“BELIEVE”，是“Bench to Bed 增强淋巴细胞输注到 工程师病毒根除”。一名被称为“柏林病人”的人被认为艾滋病毒已被治愈， 在没有抗逆转录病毒（ARV）治疗的情况下，没有证据表明病毒具有活跃的复制能力。这 “密西西比”婴儿最初似乎是另一种治疗方法，但抗逆转录病毒药物几年后病毒再次出现 停止。抗逆转录病毒疗法可延长寿命，但预期寿命差距表明接受病毒抑制疗法的患者 寿命较短，合并症较多。为了帮助结束这种流行病，需要治愈艾滋病毒。 目前的“休克和杀戮”策略在利用免疫力来寻找和清除方面受到限制。 潜伏细胞。尽管具有治疗作用，但可以通过疫苗接种来增强免疫力 迄今为止，疫苗接种对艾滋病毒感染的效果有限。此外，HIV感染者的免疫效应 接受抗逆转录病毒治疗的人尚未完全康复。至少存在三种机制 免疫系统无法完全清除病毒：（1）细胞毒性T-减弱且耗尽 发生表位逃逸的淋巴细胞 (CTL) 反应，(2) 过度激活但表现不佳 自然杀伤细胞，以及（3）效应细胞无法到达潜伏病毒所在的正确位点。 我们的提案具有广泛的目标，旨在了解如何增强杀伤能力 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 成人和儿童艾滋病毒感染中抗体介导的效应器。首先，我们会立即 使用我们最有前途的 T 细胞输注和潜伏期逆转组合启动一项试点临床研究 代理。我们将把这种组合与增强的天然和工程 T 细胞进行比较，以根除 HIV 储库（体外、小鼠、非人类灵长类动物以及其他人类临床研究），联合 新型 HIV Nef 小分子抑制剂。其次，我们将开发和测试增强型自然杀伤细胞 有或没有广泛中和抗体（在小鼠、非人灵长类动物和人类中）。第三，我们将 通过将 CTL 定位到储存库位点，CTL 无法到达病毒潜伏期的目标位点。 我们聚集了一批经验丰富的研究人员，具有强大的合作历史，以及 社区顾问。大约 40% 的科学领导职位是女性，而且 早期和少数研究人员的代表，以及两个企业合作伙伴，都受到这一信念的驱动 治愈方法将取决于增强抗艾滋病毒免疫力以及逆转潜伏期。