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

摘要 存在含有整合的、复制能力强的病毒的细胞库，这种病毒在长期的 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 ART中断后病毒复制的初始事件是治愈艾滋病毒感染的关键障碍。因此， 迫切需要新的治疗策略来消除这些障碍。的主要假设 清除HIV是：(I)CD8+T细胞和NK细胞抗病毒功能降低和/或功能障碍，与 最近描述的CD8+T细胞介导的HIV转录沉默，有利于HIV在抗逆转录病毒治疗和 如果ART停止，防止病毒血症的控制；以及(Ii)诱导有效CD8+T细胞、NK细胞的新方法， 和抗体依赖的细胞毒性(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/或根除。清除HIV首要目标是识别 HIV持续存在的新机制，并在最相关的临床前动物模型中进行测试 机械导向、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包括三个高度集成的研究焦点(RFS)。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限制性的、抗原特异性的反应，直接消除病毒感染的细胞，以及非MHC HIV转录的限制性、非溶细胞性沉默。因此，RF1将为 在RF2和RF3中测试的干预措施。RF2将使用ART治疗的HIV感染的动物模型来(I)恢复CD8+ 联合使用α-IL-10和IL-15超级激动剂(N-803)策略实现T和NK细胞功能；(Ii)靶向反弹 通过使用CD4模拟化合物(CD4mc)增强表达HIV env的细胞的抗体识别 以及(Iii)确定是否通过α-IL-10和N-干扰素提高CD8T和NK细胞的功能。 803与CD4mc协同清除感染细胞。RF3将确定是否抑制延迟提升 CD8+T细胞的活性，结合N-803和促进细胞凋亡的干预措施(Bcl-2抑制剂)或免疫- 对已重新激活病毒的细胞的介导性清除(CD4mc)将减小储存库大小。总而言之，我们将利用 RF1中产生的机制数据与RF2和RF3中的体内干预之间的协同作用 验证针对抗逆转录病毒治疗期间艾滋病毒持续和抗逆转录病毒治疗中断后艾滋病毒复发的策略。 消除艾滋病毒得到了艾滋病毒倡导(姐妹之爱)专家的支持；识别和杀死艾滋病毒环境表达 细胞(Finzi/Sodroski)；T和NK细胞生物学(Sekaly/Ribeiro/Deleage/Parsons)；水库分析和潜伏期 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)；以及治疗学开发(Merck和 免疫生物)用于治疗艾滋病毒。我们相信，拟议的机械性临床前工作将 告知可在临床试验中翻译的策略，以实现PWH病毒的长期缓解。

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.