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: 10469504
• 负责人: Deanna A Kulpa
• 金额: $ 541.23万
• 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/10469504
• 关键词: Address; Advocacy; Aftercare; Animal Model; Animals; Antibodies; 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; Persons; 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; 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.

摘要 存在一个携带整合的、有复制能力的病毒的细胞库，这些病毒在长期作用下持续存在。 长期而言，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 抗逆转录病毒疗法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，在本发明中， 迫切需要消除这些障碍的新的治疗策略。的首要假设 ERASE HIV是：（i）CD 8 + T细胞和NK细胞抗病毒功能降低和/或功能障碍， 最近描述的CD 8 + T细胞介导的HIV转录沉默有利于ART下的HIV持续存在， 如果ART停止，阻止对病毒血症的控制;和（ii）新的方法，以引发有效的CD 8 + T细胞，NK细胞， 和抗体依赖性细胞毒性（ADCC）功能，同时抑制CD 8 + T细胞介导的病毒 沉默将促进HIV的缓解和/或根除。ERASE HIV的首要目标是识别 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： 机械导向的，社区支持的治疗策略，最终可以转化为治愈 人类艾滋病毒感染。ERASE HIV包括三个高度整合的研究重点（RF）。RF 1的目标是 鉴定CD 8 + T细胞的两种不同抗病毒活性的分子和细胞机制： MHC限制的Ag特异性反应，直接消除病毒感染的细胞，和非MHC HIV转录的限制性非细胞溶解沉默。因此，RF 1将为 在RF 2和RF 3中测试的干预措施。RF 2将使用ART治疗的HIV感染动物模型，以（i）恢复CD 8 + 联合α-IL-10和IL-15超激动剂（N-803）策略的T和NK细胞功能;（ii）靶向反弹 通过使用CD 4模拟化合物（CD 4 mc）增强表达HIV Env的细胞的抗体识别， 以及它们通过ADCC的消除;以及（iii）确定是否通过α-IL-10和N- 803与CD 4 mc协同清除感染细胞。RF 3将确定延迟促进的抑制是否 CD 8 + T细胞的活性，再加上N-803和干预措施，以促进细胞凋亡（Bcl-2抑制剂）或免疫， 介导的去除（CD 4 mc）具有再活化病毒的细胞将减小储库大小。总之，我们将利用 RF 1中生成的机制数据与RF 2和RF 3中的体内干预之间的协同作用， 确认一项战略，既针对抗逆转录病毒治疗期间艾滋病毒的持续存在，也针对抗逆转录病毒治疗中断后艾滋病毒的复发。 ERASE HIV由HIV倡导专家（SisterLove）支持;识别和杀死HIV Env表达 细胞（Finzi/Sodroski）; T和NK细胞生物学（Sekaly/Ribeiro/Deleage/Parsons）;储库测定和潜伏期 模型（Kulpa/Jones/Litchterfeld/豪厄尔）;临床前动物研究（Paiardini/Silvestri/Garcia/Saez- Cirion/Keele/Kumar）;数学建模（Davenport）;和治疗开发（Merck和 ImmunityBio）用于HIV治愈。我们相信，拟议的机械导向的临床前工作将 为临床试验提供信息，以延长PWH的病毒缓解期。