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HIV缓解并促进抗逆转录病毒治疗 停止治疗（ART）。到目前为止，具有CCR 5 β 32/β 32的异基因干细胞移植（allo-HSCT） 捐赠细胞是唯一能够治愈艾滋病毒的医疗干预措施，已报告的病例多达5例。喂， HSCT也导致HIV储库的急剧减少，即使使用非突变的CCR 5供体细胞。 自体CCR 5修饰的CD 4 T细胞的被动转移已经成为一种更实惠，风险更低， 替代恢复HIV难治性免疫细胞环境。在本提案中，我们将定义主机的角色 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 IciStem将从三个独立的研究人群中获取PBMC和血浆以及临床元数据： 队列（allo-HSCT）和2个输注自体CCR 5修饰的CD 4 T细胞的受试者队列。我们 假设干预前血浆环境（微生物群相关代谢物和细胞因子）允许 allo-HSCT和自体CCR 5修饰的CD 4 T细胞的植入更好， 减少HIV储库和CD 4和CD 8记忆干细胞（Tscm）和效应细胞以及先天性 细胞抗病毒反应，限制艾滋病毒反弹后ATI。在aim 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频率 病毒序列、整合位点和翻译能力的完整性在持久的病毒感染过程中普遍存在， 控制预干预，并可能影响病毒载量反弹和免疫重建的动力学 植入后。在目标2中，我们将确定东道国环境对东道国-捐助国规模的影响 嵌合、先天免疫激活和干细胞样CD 4 + T细胞相关的免疫重建。我们 初步数据显示，HIV耐药CD 4 TSCM的频率是长期控制的最佳预测因子 自体CD 4 T细胞过继转移后的病毒载量。微生物和宿主代谢物是重要的 先天性和适应性免疫细胞的分化和效应子功能的调节剂。因此，选择亲- 炎症代谢物可能会影响这些T细胞干细胞的发育， 通过促进骨髓细胞的活化和分化，这将阻碍骨髓移植。在aim 3中 我们将定义与自体移植后病毒控制相关的平行病毒学和代谢机制， CCR 5修饰的CD 4 + T细胞疗法和全HSCT干预。上面列出的病毒学特征，以及 目标1和2中引用的宿主和环境特征将影响自体HIV抗性的过继转移 CD 4 T细胞，就像BMT一样。实验设计包括病毒学、免疫学和多体切割 边缘技术将被整合，以提供关于宿主作用的新的经验证的机制证据 在HIV治疗策略中，影响对基于免疫细胞的疗法的反应异质性的因素。

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.