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: 9976444
• 负责人: R. Brad Jones
• 金额: $ 568.07万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976444
• 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; 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; 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; comorbidity; 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）” 射频消融我们称我们的应用程序为“相信”，简称“台床增强淋巴细胞输注， 工程师病毒根除”。其中一名被称为“柏林病人”的人被认为治愈了艾滋病毒， 没有证据表明在没有抗逆转录病毒（ARV）治疗的情况下存在活跃复制能力的病毒。的 “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 停止抗逆转录病毒治疗延长寿命，但预期寿命差距显示患者接受病毒抑制治疗 活得更短，有更多的并发症。为了帮助结束这一流行病，需要一种艾滋病毒治疗方法。 目前的“休克和杀死”战略在利用免疫力寻找和消除 潜伏细胞免疫力的增强可以通过接种疫苗来进行，尽管治疗性 迄今为止，HIV感染的疫苗接种效果有限。此外，HIV感染者的免疫效应物 这些人在抗逆转录病毒治疗后没有完全康复。至少有三种机制导致 免疫系统无法完全清除病毒：（1）细胞毒性T细胞减弱和耗尽， 发生表位逃逸的淋巴细胞（CTL）应答，（2）过度活化但表现不佳 自然杀伤细胞，和（3）效应细胞无法到达潜伏病毒所在的正确部位。 我们的建议有广泛的目标，旨在了解如何提高杀伤能力 HIV特异性细胞毒性T淋巴细胞，以增强NK细胞功能，并利用T细胞，NK细胞和 在成人和儿童HIV感染的背景下，抗体介导的效应物。首先，我们将立即 启动了一项初步临床研究，采用我们最有前途的T细胞输注和潜伏期逆转组合 剂.我们将把这种组合与增强的天然和工程T细胞进行比较，以根除艾滋病毒 储库（体外、小鼠、非人灵长类动物和其他人类临床研究），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， 具有或不具有广泛中和抗体（在小鼠、非人灵长类动物和人中）。三是 通过靶向CTL以归巢至储库位点，靶向CTL不能到达的病毒潜伏位点。 我们聚集了一群有成就的调查人员，他们有着很强的合作历史，沿着着 社区顾问。大约40%的科学领导职位是妇女， 早期阶段和少数民族调查人员的代表，以及两个企业合作伙伴，都是由信念驱动的， 治愈将取决于增强与潜伏期逆转相关的抗HIV免疫力。

项目成果

HIV-1-Specific Chimeric Antigen Receptor T Cells Fail To Recognize and Eliminate the Follicular Dendritic Cell HIV Reservoir In Vitro.

HIV-1 特异性嵌合抗原受体 T 细胞无法在体外识别并消除滤泡树突状细胞 HIV 储库。

• DOI: 10.1128/jvi.00190-20
• 发表时间: 2020
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Ollerton,MatthewT;Berger,EdwardA;Connick,Elizabeth;Burton,GregoryF
• 通讯作者: Burton,GregoryF

HIV Receives a "One Two Knockout Punch".

HIV 受到“一二击倒”。

• DOI: 10.1016/j.ymthe.2017.02.001
• 发表时间: 2017
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Cruz,ConradRussell;Bollard,CatherineM
• 通讯作者: Bollard,CatherineM

Current challenges and recent advances in the search for a cure for HIV.

寻找艾滋病毒治疗方法的当前挑战和最新进展。

• DOI: 10.1002/jia2.25248
• 发表时间: 2019
• 期刊: Journal of the International AIDS Society
• 影响因子: 6
• 作者: Jones,RBrad

Antiretroviral drug activity and potential for pre-exposure prophylaxis against COVID-19 and HIV infection.

• DOI: 10.1080/07391102.2021.1901144
• 发表时间: 2022-10
• 期刊: Journal of biomolecular structure & dynamics
• 影响因子: 4.4
• 作者: Copertino DC Jr;Casado Lima BC;Duarte RRR;Powell TR;Ormsby CE;Wilkin T;Gulick RM;de Mulder Rougvie M;Nixon DF
• 通讯作者: Nixon DF

Phylogenetic approach to recover integration dates of latent HIV sequences within-host.

• DOI: 10.1073/pnas.1802028115
• 发表时间: 2018-09-18
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Jones BR;Kinloch NN;Horacsek J;Ganase B;Harris M;Harrigan PR;Jones RB;Brockman MA;Joy JB;Poon AFY;Brumme ZL
• 通讯作者: Brumme ZL