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: 9190794
• 负责人: DOUGLAS F NIXON
• 金额: $ 571.55万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190794
• 关键词: Adherence; Adult; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Applications Grants; B-Lymphocytes; BLR1 gene; Basic Science; Beds; Belief; Berlin; Cell physiology; Cells; Child; Clear Cell; 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; Staging; T-Lymphocyte; Testing; Therapeutic; Translations; Vaccination; Viral; Viral reservoir; Virus; Virus Latency; Woman; abstracting; antibody engineering; antiretroviral therapy; autologous lymphocytes; collaboratory; design; drug resistant virus; exhaust; improved; in vivo; inhibitor/antagonist; insight; killings; minority investigator; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel strategies; pediatric human immunodeficiency virus infection; pre-clinical; research study; 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。 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 没有证据表明在没有抗逆转录病毒（ARV）治疗的情况下，有效复制病毒 “密西西比”婴儿最初似乎是另一种治疗方法，但病毒在ARV几年后重新出现 停止疗法。 过着较短的生活，并有更多的合并症来帮助结束流行病，需要治疗。 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 潜在细胞可以通过疫苗接种进行增强 迄今为止，艾滋病毒感染的疫苗有限。 ARV治疗未完全恢复人。 免疫系统无法完全清除维鲁us：（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，其目的是使如何杀人能力 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 抗体介导的效应子，首先，我们将立即 通过我们最有希望的T细胞Infusl IND延迟延迟的结合来启动一项试点临床研究 代理人。 储层（在体外，在小鼠，非人类灵长类动物和其他人类临床研究中） 使用新型HIV NEF小分子抑制剂。 有或没有广泛中和抗体（在小鼠，人类灵长类动物和人类中） CTL无法达到病毒潜伏期的目标位点，通过将CTL靶向在家中。 我们收集了一群成群的调查员，以及有着强大的协作历史，以及 社区顾问。 代表阶段和少数族裔调查员以及两个公司合作伙伴，都受到信念的驱动 与潜伏期逆转相关的抗HIV IMUNITH的治疗方法将交付。