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: 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
• 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

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 存在具有综合复制能力的病毒的细胞储层，该病毒持续存在 术语，完全抑制性抗逆转录病毒疗法（ART）和宿主免疫反应无法控制 遵循ART中断的病毒复制的初始事件是治愈HIV感染的关键障碍。那， 需要非常需要进行清除这些障碍的新型热策略。总体假设 擦除HIV是：（i）减少和/或功能失调的CD8+ T和NK细胞抗病毒功能，并结合 最近描述的CD8+ T细胞介导的艾滋病毒的转录沉默，在ART和 如果停止艺术，请防止病毒血症的控制； （ii）引起有效CD8+ T细胞的新型方法NK细胞， 和抗体依赖性细胞毒性（ADCC）功能，同时抑制CD8+ T细胞介导的病毒 沉默将促进艾滋病毒的缓解和/或辐射。擦除艾滋病毒的总体目标是确定 HIV持久性的新型机制，并通过最相关的临床前动物模型测试它们 机械方向的，社区支持的治疗策略，最终可以翻译成治疗 人类的艾滋病毒感染。擦除HIV包括三个高度综合的研究焦点（RFS）。 RF1针对 确定CD8+ T细胞两种不同抗病毒活性的基础的分子和细胞机制： MHC限制的Ag特异性反应直接消除了病毒感染的细胞，非MHC 受HIV转录的限制，非溶血沉默。因此，RF1将为 在RF2和RF3中测试的干预措施。 RF2将使用经过艺术处理的HIV感染的动物模型来恢复CD8+ T和NK细胞功能具有组合的α-IL-10和IL-15超级飞机（N-803）策略； （ii）目标反弹 通过使用CD4模拟化合物（CD4MC）来增强表达HIV Env的细胞的抗体识别的病毒 以及他们通过ADCC淘汰； （iii）确定是否通过α-IL-10和N-改善CD8和NK细胞功能 803与CD4MC协同以清除感染细胞。 RF3将确定抑制潜伏期的抑制 CD8+ T细胞的活性，与N-803结合以及促进凋亡的干预措施（Bcl-2抑制剂）或免疫 - 已重新激活病毒的细胞的介导的去除（CD4MC）将减少储层大小。总的来说，我们将利用 RF1中生成的机械数据与RF2和RF3中的体内干预措施之间的协同作用 验证一种旨在针对ART期间艾滋病毒持久性和艾滋病毒复发后的策略。 擦除艾滋病毒得到艾滋病毒倡导专家的支持（sisterlove）；识别和杀死HIV表达的 细胞（Finzi/Sodroski）; T和NK细胞生物学（Sekaly/Ribeiro/Dreage/Parsons）；水库测定和潜伏期 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）；和治疗开发（默克和 艾滋病毒治疗的免疫。我们认为，拟议的机械方向前临床前工作将 告知可以在临床试验中翻译的策略，以实现PWH的长时间病毒缓解。