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对“马丁·德莱尼艾滋病毒治疗研究合作实验室(UM1)”的响应。 RFA。我们将我们的应用程序称为“Believe”，缩写为“BASE TO BED ENTERED LANCEL INTERVATION TO 工程师根除病毒“。一名被称为“柏林患者”的人被认为已经治愈了艾滋病毒， 在没有抗逆转录病毒(ARV)治疗的情况下，没有证据表明具有活跃复制能力的病毒。这个 “密西西比”婴儿最初似乎是另一种治愈方法，但病毒在ARV后几年再次出现。 停止。抗逆转录病毒疗法可以延长生命，但预期寿命差距显示患者接受病毒抑制疗法 活得更短，有更多的共病。为了帮助结束这种流行病，需要一种治疗艾滋病毒的方法。 目前的“电击和杀戮”策略在利用寻找和清除免疫的力量方面是有限的。 潜伏细胞。增强免疫力可以通过接种疫苗来实现，尽管这是有治疗作用的 到目前为止，艾滋病毒感染的疫苗接种效果有限。此外，免疫效应器在HIV感染者中 接受抗逆转录病毒治疗的人不能完全康复。至少有三种机制会导致 免疫系统不能完全清除病毒：(1)虚弱和耗尽的细胞毒性T细胞- 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置。 我们的提案有广泛定义的目标，旨在了解如何增强杀戮能力 HIV特异性细胞毒T淋巴细胞，增强NK细胞功能，利用T细胞，NK细胞和 成人和儿童艾滋病毒感染背景下的抗体介导的效应器。首先，我们将立即 使用我们最有希望的T细胞输注和潜伏期逆转组合启动一项试点临床研究 探员们。我们将把这种组合与增强的天然T细胞和工程T细胞进行比较，以根除艾滋病毒 储存库(体外、小鼠、非人类灵长类动物和其他人类临床研究) 使用新型HIV Nef小分子抑制剂。第二，我们将开发和测试增强型自然杀伤细胞 使用或不使用广谱中和抗体(在老鼠、非人类灵长类动物和人类中)。第三，我们将 通过将CTL靶向到宿主储存区，来定位CTL无法到达的病毒潜伏期的靶点。 我们聚集了一批有经验的调查人员，他们有很强的合作历史，以及 社区顾问。大约40%的科学领导职位是女性，有 早期和少数族裔调查人员的代表，以及两个公司合作伙伴，都是由这样的信念驱动的 治愈将取决于增强与潜伏期逆转相关的抗艾滋病毒免疫力。

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

Integrated Assessment of Viral Transcription, Antigen Presentation, and CD8+ T Cell Function Reveals Multiple Limitations of Class I-Selective Histone Deacetylase Inhibitors during HIV-1 Latency Reversal.

病毒转录、抗原呈递和 CD8 T 细胞功能的综合评估揭示了 I 类选择性组蛋白脱乙酰酶抑制剂在 HIV-1 潜伏期逆转过程中的多重局限性。

• DOI: 10.1128/jvi.01845-19
• 发表时间: 2020
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Mota,TaliaM;McCann,ChaseD;Danesh,Ali;Huang,Szu-Han;Magat,DeanB;Ren,Yanqin;Leyre,Louise;Bui,TracyD;Rohwetter,ThomasM;Kovacs,ColinM;Benko,Erika;MacLaren,Lynsay;Wimpelberg,Avery;Cannon,ChristopherM;Hardy,WDavid;Safrit,J
• 通讯作者: Safrit,J