MultiOMICS to uncover immune and virological mechanisms that drive HIV DNA decay, restore immune homeostasis, and promote HIV specific immunity in PWH receiving cell therapies.

摘要 基于免疫细胞的疗法被认为能够诱导艾滋病毒缓解并促进抗逆转录病毒 停止治疗(ART)。到目前为止，CCR5∆32/∆32的异基因干细胞移植 捐献细胞是唯一能够治愈多达五个报告病例中的艾滋病毒的医学干预措施。你好啊- 即使在使用非突变的CCR5供体细胞的情况下，HSCT也会导致艾滋病毒储存库的急剧减少。 被动移植自体CCR5修饰的CD4T细胞已经成为一种更负担得起、风险更小、 恢复艾滋病毒耐药免疫细胞环境的替代方案。在本提案中，我们将定义主持人的角色 环境(包括宿主/非宿主代谢物)对病毒学和免疫学结果的影响。为此，我们 将访问来自三个独立研究群体的PBMC和血浆以及临床元数据：IciStem 队列(allo-HSCT)和2组受试者输注自体CCR5修饰的CD4T细胞。我们 假设预先干预的血浆环境(微生物区系相关代谢物和细胞因子)允许 异基因造血干细胞移植和CCR5修饰的自体CD4T细胞更好地植入与 减少HIV储存和恢复CD4和CD8记忆干细胞(Tscm)和效应细胞以及先天的 限制HIV在ATI上反弹的细胞抗病毒反应。在目标1中，我们将确定主机的影响 驱动病毒学特征异质性的环境，包括具有完整前病毒的细胞的频率 在病毒长期持续期间普遍存在的病毒序列、整合位点和翻译能力的完整性 控制预干预对病毒载量反弹和免疫重建动力学的影响 贴花。在目标2中，我们将确定宿主环境对宿主-供体大小的影响 嵌合体、先天免疫激活和干细胞样CD4+T细胞相关的免疫重建。我们的 初步数据显示，抗HIV的CD4TSCM频率是长期控制的最佳预测因子 自体CD4T细胞过继转移后病毒载量的变化。微生物和宿主代谢物很重要 先天免疫细胞和获得性免疫细胞分化和效应功能的调节器。因此选择了PRO- 炎性代谢产物可能会影响这些T细胞干细胞的发育，并对艾滋病毒产生抵抗力 通过促进髓系细胞的活化和分化，这将阻碍骨髓的植入。在AIM 3中 我们将定义与自体后病毒控制相关的平行病毒学和代谢机制 CCR5改良的CD4+T细胞治疗和ALL-HSCT干预。上面列出的病毒学特征，以及 AIMS 1和2中引用的宿主和环境特征将影响自体HIV耐药的收养转移 CD4T细胞，就像骨髓移植一样。实验设计包括病毒学、免疫学和多组体切割。 将集成的边缘技术，以提供关于主机角色的新的、经过验证的机制证据 艾滋病毒治疗策略中影响免疫细胞治疗反应异质性的因素。

ABSTRACT Immune cell-based therapies have been postulated to be able to induce HIV remission and facilitate antiretroviral therapy (ART) discontinuation. To date, allogeneic stem cell transplantation (allo-HSCT) with CCR5∆32/∆32 donor cells is the only medical intervention that has been able to cure HIV in up to five reported cases. Allo- HSCT also results in a dramatic reduction in the HIV reservoir even when using non-mutated CCR5 donor cells. Passive transfer of autologous CCR5-modified CD4 T cells has emerged as a more affordable, less-risky, alternative to reinstate an HIV-refractory immune cell milieu. In this proposal we will define the role of the host environment (including host/non-host metabolites) on virological and immunological outcomes. To this end we will access PBMCs and plasma, and clinical metadata from three independent study populations: the IciStem cohort (allo-HSCT) and 2 cohorts of subjects infused with autologous CCR5-modified CD4 T cells. We hypothesize that a pre-intervention plasma milieu (microbiota associated metabolites and cytokines) allows for better engraftment of both allo-HSCT and autologous CCR5-modified CD4 T cells which is associated with reduced HIV reservoir and rejuvenation of CD4 and CD8 memory stem cells (Tscm) and effector cells and innate cell antiviral responses that limit HIV rebound upon ATI. In aim1 we will identify the impact of the host environment driving the heterogeneity of virological features including frequencies of cells with intact provirus integrity of viral sequences, integration sites and translation competence prevalent during long-lasting viral control pre-intervention and which can impact on the kinetics of viral load rebound and immune reconstitution post engraftment. In aim 2 we will identify the impact of host environment on the magnitude of host-donor chimerism, innate immune activation and stem-like CD4+ T-cell associated immune reconstitution. Our preliminary data show that frequencies of HIV resistant CD4 TSCM are the best predictors of long-term control of viral load post adoptive transfer of autologous CD4 T cells. Microbial and host metabolites are important modulators of the differentiation and effector function of innate and adaptive immune cells. Hence selected pro- inflammatory metabolites could impact on the development of these T cell stem cells and as well HIV resistant myeloid cells by promoting their activation and differentiation and this will impede on BM engraftment. In aim 3 we will define parallel virological and metabolic mechanisms that are associated with viral control post autologous CCR5 modified CD4+ T-cell therapy and all-HSCT intervention. The virological features listed above, and the host and environmental features cited in Aims 1 and 2 will impact on adoptive transfer of autologous HIV resistant CD4 T cells as they did for BMT. The experimental design includes virology, immunology and multiomic cutting edge technologies which will be integrated to provide novel validated mechanistic evidence as to the role of host factors in shaping the heterogeneity of the response to immune cell-based therapies in HIV cure strategies.