Enterprise for Research and Advocacy to Stop and Eradicate HIV (ERASE-HIV)

阻止和根除艾滋病毒研究和倡导企业 (ERASE-HIV)

基本信息

批准号：
10313672
负责人：
Deanna A Kulpa
金额：
$ 495.49万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10313672
关键词：
Address Advocacy Aftercare Animal Model Animals Antibodies Antiviral Agents Apoptosis BCL2 gene Basic Science Biological Assay CD8-Positive T-Lymphocytes Cell physiology Cells Cellular biology Clinical Clinical Trials Communities Coupled Cytotoxic T-Lymphocytes Data Disease remission Event Excision Gene Silencing Genetic Transcription Goals HIV HIV Infections Human Immune Immune response Immunologics Immunology Infection Intercept Interleukin-10 Interleukin-15 Interruption Intervention Macaca mulatta Maintenance Mediating Modeling Molecular Natural Killer Cells Outcome Recrudescences Research Specimen T-Lymphocyte Testing Therapeutic Translating Uncertainty Universities Viral Viral reservoir Viremia Virus Virus Replication Work animal model development antibody-dependent cell cytotoxicity antiretroviral therapy base collaboratory community involvement cytotoxic drug development global health humanized mouse improved in vivo inhibitor/antagonist innovation mathematical model mimetics mouse model novel novel strategies novel therapeutic intervention pre-clinical preclinical study prevent response simian human immunodeficiency virus synergism therapeutic development viral rebound virology

项目摘要

Abstract The presence of a reservoir of cells harbouring integrated, replication-competent virus that persists under long- term, fully suppressive antiretroviral therapy (ART) and the inability of the host immune responses to control the initial events of viral replication that follow ART interruption are critical barriers to curing HIV infection. Thus, novel therapeutic strategies to remove these barriers are critically needed. The overarching hypotheses of ERASE HIV are: (i) decreased and/or dysfunctional CD8+ T and NK cell antiviral functions, combined with the recently-described CD8+ T-cell-mediated transcriptional silencing of HIV, favour HIV persistence under ART and prevent the control of viremia if ART is stopped; and (ii) novel approaches to elicit effective CD8+ T-cell, NK cell, and antibody-dependent cellular cytotoxicity (ADCC) functions while inhibiting the CD8+ T-cell-mediated virus silencing will promote remission and/or eradication of HIV. The overarching goal of ERASE HIV is to identify novel mechanisms of HIV persistence and to test them in the most relevant pre-clinical animal models through mechanistically-oriented, community-supported therapeutic strategies that can be ultimately translated to cure HIV infection in humans. ERASE HIV includes three highly integrated Research Foci (RFs). RF1 is aimed at identifying the molecular and cellular mechanisms underlying the two distinct antiviral activities of CD8+ T-cells: the MHC-restricted, Ag-specific response that directly eliminates virus-infected cells, and the non-MHC restricted, non-cytolytic silencing of HIV transcription. As such, RF1 will provide the conceptual basis for the interventions tested in RF2 and RF3. RF2 will use animal models of ART-treated HIV infection to (i) restore CD8+ T and NK cell function with a combined α-IL-10 and IL-15 superagonist (N-803) strategy; (ii) target rebounding virus by using a CD4-mimetic compound (CD4mc) to enhance antibody recognition of cells expressing HIV Env and their elimination via ADCC; and (iii) determine if improving CD8 T and NK cell function via α-IL-10 and N- 803 synergizes with CD4mc to clear infected cells. RF3 will determine if suppression of the latency-promoting activity of CD8+ T-cells, coupled with N-803 and interventions to promote apoptosis (Bcl-2 inhibitors) or immune- mediated removal (CD4mc) of cells that have reactivated virus, will reduce the reservoir size. In all, we will exploit the synergy between the mechanistic data generated in RF1 and the in vivo interventions in RF2 and RF3 to validate a strategy that targets both HIV persistence during ART and HIV recrudescence after ART interruption. ERASE HIV is supported by experts in HIV advocacy (SisterLove); recognition and killing of HIV Env-expressing cells (Finzi/Sodroski); T and NK cell biology (Sekaly/Ribeiro/Deleage/Parsons); reservoir assays and latency models (Kulpa/Jones/Litchterfeld/Howell); pre-clinical animal studies (Paiardini/Silvestri/Garcia/Saez- Cirion/Keele/Kumar); mathematical modelling (Davenport); and therapeutics development (Merck and ImmunityBio) for HIV cure. We believe that the proposed mechanistically-oriented pre-clinical work will inform strategies that can be translated in clinical trials to achieve prolonged viral remission in PWH.

抽象的存在一个含有整合的、具有复制能力的病毒的细胞库，该病毒在长期存在下持续存在。术语，完全抑制性抗逆转录病毒治疗（ART）和宿主免疫反应无法控制 ART 中断后病毒复制的初始事件是治愈 HIV 感染的关键障碍。迫切需要消除这些障碍的新治疗策略。消除 HIV 是：(i) CD8+ T 和 NK 细胞抗病毒功能降低和/或功能失调，并结合最近描述的 CD8+ T 细胞介导的 HIV 转录沉默有利于 HIV 在 ART 下的持续存在，并且如果停止 ART，则无法控制病毒血症；以及 (ii) 诱导有效 CD8+ T 细胞、NK 细胞、和抗体依赖性细胞毒性 (ADCC) 在抑制 CD8+ T 细胞介导的病毒的同时发挥作用沉默将促进艾滋病毒的缓解和/或根除消除艾滋病毒的首要目标是识别艾滋病毒。 HIV持续存在的新机制，并通过以下方法在最相关的临床前动物模型中对其进行测试以机械为导向、社区支持的治疗策略，最终可以转化为治愈 ERASE HIV 包括三个高度整合的研究焦点 (RF1)。确定 CD8+ T 细胞两种不同抗病毒活性背后的分子和细胞机制：直接消除病毒感染细胞的 MHC 限制性 Ag 特异性反应，以及非 MHC 因此，RF1 将为 HIV 转录的限制性、非溶细胞性沉默提供概念基础。对测试的 RF2 和 RF3 的干预措施将使用 ART 治疗的 HIV 感染动物模型来 (i) 恢复 CD8+。 T 和 NK 细胞通过联合 α-IL-10 和 IL-15 超级激动剂 (N-803) 策略发挥作用；(ii) 目标反弹；通过使用 CD4 模拟化合物 (CD4mc) 来增强表达 HIV Env 的细胞的抗体识别病毒以及通过 ADCC 消除它们；以及 (iii) 确定是否通过 α-IL-10 和 N- 改善 CD8 T 和 NK 细胞功能 803 与 CD4mc 协同清除感染细胞将决定是否抑制潜伏期促进。 CD8+ T 细胞的活性，结合 N-803 和促进细胞凋亡（Bcl-2 抑制剂）或免疫的干预措施介导的清除（CD4mc）已重新激活病毒的细胞，将减少储存库的大小。 RF1 中生成的机械数据与 RF2 和 RF3 中的体内干预之间的协同作用验证针对 ART 期间 HIV 持续存在和 ART 中断后 HIV 复发的策略。 ERASE HIV 得到了 HIV 倡导专家 (SisterLove) 的支持；识别和消灭 HIV Env 表达者；细胞（Finzi/Sodroski）；T 和 NK 细胞生物学（Sekaly/Ribeiro/Deleage/Parsons）；模型（Kulpa/Jones/Litchterfeld/Howell）；临床前动物研究（Paiardini/Silvestri/Garcia/Saez- Cirion/Keele/Kumar）；数学建模（Davenport）和治疗方法开发（默克和 ImmunityBio）用于艾滋病毒治疗，我们相信所提出的以机械为导向的临床前工作将会实现。提供可在临床试验中转化的策略，以在感染者卫生保健中实现长期病毒缓解。