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)

• 批准号: 10609920
• 负责人: Deanna A Kulpa
• 金额: $ 563.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10609920
• 关键词: Address; Advocacy; Aftercare; Animal Model; Animals; Antibodies; Apoptosis; BCL2 gene; Basic Science; Binding; 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; Persons; Recrudescences; Research; Specimen; T-Lymphocyte; Testing; Therapeutic; Translating; Uncertainty; Universities; Viral; Viral Physiology; Viral reservoir; Viremia; Virus; Virus Replication; Work; animal model development; antibody-dependent cell cytotoxicity; antiretroviral therapy; collaboratory; community involvement; cytotoxic; drug development; global health; improved; in vivo; inhibitor; 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

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。因此， 迫切需要新的治疗策略来消除这些障碍。总体假设 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 如果停止抗逆转录病毒治疗，就会阻碍病毒血症的控制； (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。 ERASE HIV 的总体目标是确定 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 以机制为导向、社区支持的治疗策略，最终可以转化为治愈 人类感染艾滋病毒。 ERASE HIV 包括三个高度整合的研究焦点 (RF)。 RF1的目标是 确定 CD8+ T 细胞两种不同抗病毒活性的分子和细胞机制： MHC 限制性 Ag 特异性反应直接消除病毒感染的细胞，而非 MHC HIV转录的限制性、非溶细胞性沉默。因此，RF1 将为 RF2 和 RF3 中测试了干预措施。 RF2 将使用经 ART 治疗的 HIV 感染动物模型来 (i) 恢复 CD8+ 通过联合 α-IL-10 和 IL-15 超级激动剂 (N-803) 策略发挥 T​​ 和 NK 细胞功能； (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； (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 协同清除受感染的细胞。 RF3 将确定是否抑制延迟促进 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，将减少病毒库的大小。总而言之，我们将利用 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；识别并杀死表达 HIV Env 的病毒 细胞（Finzi/Sodroski）； T 和 NK 细胞生物学（Sekaly/Ribeiro/Deleage/Parsons）；储库分析和潜伏期 模型（Kulpa/Jones/Litchterfeld/Howell）；临床前动物研究（Paiardini/Silvestri/Garcia/Saez- 奇里昂/基尔/库马尔）；数学建模（达文波特）；和疗法开发（默克和 ImmunityBio）用于治疗艾滋病毒。我们相信，所提出的以机械为导向的临床前工作将 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。

项目成果

Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators.

• DOI: 10.3389/fimmu.2021.768695
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Reece MD;Taylor RR;Song C;Gavegnano C
• 通讯作者: Gavegnano C

Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control.

• DOI: 10.1172/jci157549
• 发表时间: 2022-06-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Perdomo-Celis, Federico;Passaes, Caroline;Monceaux, Valerie;Volant, Stevenn;Boufassa, Faroudy;de Truchis, Pierre;Marcou, Morgane;Bourdic, Katia;Weiss, Laurence;Jung, Corinne;Bourgeois, Christine;Goujard, Cecile;Meyer, Laurence;Muller-Trutwin, Michaela;Lambotte, Olivier;Saez-Cirion, Asier
• 通讯作者: Saez-Cirion, Asier

Novel role of UHRF1 in the epigenetic repression of the latent HIV-1.

• DOI: 10.1016/j.ebiom.2022.103985
• 发表时间: 2022-05
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Verdikt, Roxane;Bendoumou, Maryam;Bouchat, Sophie;Nestola, Lorena;Pasternak, Alexander O.;Darcis, Gilles;Avettand-Fenoel, Veronique;Vanhulle, Caroline;Ait-Ammar, Amina;Santangelo, Marion;Plant, Estelle;Le Douce, Valentin;Delacourt, Nadege;Necsoi, Coca;Corazza, Francis;Passaes, Caroline Pereira Bittencourt;Schwartz, Christian;Bizet, Martin;Fuks, Francois;Saez-Cirion, Asier;Rouzioux, Christine;De Wit, Stephane;Berkhout, Ben;Gautier, Virginie;Rohr, Olivier;Van Lint, Carine
• 通讯作者: Van Lint, Carine