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.

MultiOMICS 旨在揭示驱动 HIV DNA 衰变的免疫和病毒学机制，恢复免疫稳态，并促进接受细胞疗法的感染者的 HIV 特异性免疫。

• 批准号: 10731666
• 负责人: Javier Martinez-Picado
• 金额: $ 20.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731666
• 关键词: Adoptive Transfer; Allogenic; Anti-Retroviral Agents; Antiviral Response; Autologous; Automobile Driving; Berlin; Bile Acids; Binding; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Case Study; Cell Differentiation process; Cell Therapy; Cell physiology; Cells; Chimerism; Cities; Citric Acid Cycle; Clinical; Clinical Trials; Competence; Complex; Cytotoxic T-Lymphocytes; DNA; DNA Sequence Alteration; Data; Disease remission; Donor person; Effector Cell; Engraftment; Environment; Epigenetic Process; Experimental Designs; Extravasation; Fatty Acids; Flow Cytometry; Frequencies; Genetic Transcription; HIV; HIV resistance; HIV-1; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Heterogeneity; Homeostasis; Immune; Immune response; Immunity; Immunologics; Immunology; Immunotherapy; Individual; Infection; Inflammatory; Infusion procedures; Innate Immune Response; Integration Host Factors; Interruption; Intervention; Kinetics; Life; London; Medical; Memory; Metabolic; Metadata; Monitor; Myeloid Cells; New York; Outcome; Participant; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Procedures; Proviruses; Refractory; Regimen; Rejuvenation; Reporting; Resistance; Role; Safety; Shapes; Stem cell transplant; T cell therapy; T-Cell Development; T-Lymphocyte; Technology; Testing; Translations; Validation; Viral; Viral Load result; Viral reservoir; Viremia; Virus Replication; Volatile Fatty Acids; antiretroviral therapy; cohort; cytokine; data integration; density; effector T cell; exhaustion; expectation; gut dysbiosis; high risk; immune activation; immune reconstitution; immunological intervention; in vitro Assay; integration site; latent HIV reservoir; lipidomics; metabolome; metabolomics; microbial; microbial host; microbiome; microbiota; multiple omics; novel; reconstitution; response; stem; stem cells; study population; success; viral rebound; virology

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.

抽象的 已经假定基于免疫细胞的疗法能够诱导HIV缓解并促进抗逆转录病毒 治疗（艺术）中断。迄今为止，具有CCR5Δ32/∆32的同种异体干细胞移植（Allo-HSCT） 供体细胞是唯一能够在多达五例病例中治愈HIV的唯一医疗干预措施。 all HSCT也会导致HIV储层的急剧减少，即使使用了未突出的CCR5供体细胞。 自体CCR5修饰的CD4 T细胞的被动转移已成为一种更负担得起的，不太风险的， 替代恢复HIV难治性免疫细胞环境。在此提案中，我们将定义主机的角色 环境（包括宿主/非宿主代谢产物）在病毒学和免疫学结果上。为此，我们 将访问来自三个独立研究人群的PBMC和血浆，以及临床元数据：ICISTEM 队列（Allo-HSCT）和2个被自体CCR5修饰CD4 T细胞感染的受试者。我们 假设干预前血浆环境（菌群相关的代谢产物和细胞因子）允许 更好地植入Allo-HSCT和自体CCR5修饰的CD4 T细胞，与 减少了CD4和CD8记忆干细胞（TSCM）以及效应细胞以及先天的HIV储量和恢复活力 细胞抗病毒反应限制ATI对HIV反弹。在AIM1中，我们将确定主机的影响 驱动病毒学特征异质性的环境，包括完整的病毒细胞的频率 在持久病毒期间，病毒序列，整合位点和翻译能力的完整性 控制干预前，这可能会影响病毒负荷反弹和免疫重建的动力学 爆发后。在AIM 2中，我们将确定宿主环境对宿主donor的大小的影响 嵌合，先天免疫反应和类似茎状的CD4+ T细胞相关的免疫结合。我们的 初步数据表明，抗HIV CD4 TSCM的频率是长期控制的最佳预测指标 自体CD4 T细胞的传递后，病毒载荷的转移。微生物和宿主代谢物很重要 先天性和适应性免疫细胞的分化和效应函数的调节剂。因此选择了 炎性代谢产物可能会影响这些T细胞干细胞的发展，以及抗HIV 髓样细胞通过促进其激活和分化，这会阻碍BM植入。在目标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修饰的CD4+ T细胞疗法和全HSCT干预。上面列出的病毒学特征，以及 AIM 1和2中引用的宿主和环境特征将影响自体艾滋病毒的自适应转移 与BMT一样，CD4 T细胞。实验设计包括病毒学，免疫学和多媒体切割 边缘技术将集成以提供有关宿主作用的新颖验证的机械证据 在HIV治疗策略中塑造对免疫细胞疗法反应的异质性的因素。