HIV Reservoir and Gene Modified Cell Dynamics Following Autologous Stem Cell Transplantation

自体干细胞移植后的 HIV 储库和基因修饰细胞动力学

• 批准号: 10700521
• 负责人: Timothy Jensen Henrich
• 金额: $ 80.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-13 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700521
• 关键词: AIDS Malignancy Consortium; Affect; Aftercare; Autologous; Autologous Stem Cell Transplantation; Autologous Transplantation; Biological Assay; Blood; CAR T cell therapy; CCR5 gene; CD34 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Capsid; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; DNA; Data; Disease remission; Engraftment; Enrollment; Flow Cytometry; Future; Gene Expression; Gene Modified; Genes; Genetic Transcription; HIV; HIV Infections; HIV resistance; HIV therapy; HIV-1; Hematologic Neoplasms; Hematopoietic stem cells; Human; Immune; Immunity; In Vitro; Individual; Infection; Infection prevention; Infusion procedures; Interruption; Knowledge; Lentivirus Vector; Life Cycle Stages; Lymphocyte; Lymphoma; Macaca; Maintenance; Malignant Neoplasms; Measures; Mediating; Mutation; Participant; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Population; Protocols documentation; RNA; Recrudescences; Residual state; Resistance; Reverse Transcription; Safety; Sampling; Science; Stem cell transplant; T cell receptor repertoire sequencing; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissue Expansion; Tissues; Transactivation; Transduction Gene; Transplantation; Viral; Viral reservoir; Virus; Withdrawal; antiretroviral therapy; design; experience; gene product; gene therapy; high dimensionality; immune reconstitution; improved; in vivo; innovation; insight; interest; lentiviral integration; lentiviral-mediated; longitudinal analysis; novel; phase 1 study; prevent; primary endpoint; receptor; reconstitution; single-cell RNA sequencing; small hairpin RNA; stem cell gene therapy; stem cells; stemness; viral entry inhibitor

SUMMARY/ABSTRACT: The use of autologous gene modified cells that are resistant to HIV infection to reduce viral reservoir size and delay or prevent HIV recrudescence is on the forefront of HIV curative science. However, many current gene modification approaches focus solely on reducing CCR5 expression on hematopoietic stem cells or mature CD4 T cells. These approaches may have limited impact in people with HIV (PWH) that have virus able to use other coreceptors for entry, and only provide a single layer of protection against infection in vivo. As a result, the AMC #097 study, “A Phase I Study of Stem Cell Gene Therapy for HIV Mediated by Lentivector Transduced, Pre-Selected CD34+ Cells: A Trial of the AIDS Malignancy Consortium,” was implemented to combine multiple anti-HIV genes into a single lentiviral vector that is designed to block HIV-1 infection at different stages of the HIV-1 life cycle providing strong pre-integration inhibition of HIV-1 infection using a lentiviral vector that including a CCR5 shRNA, a chimeric human-macaqueTRIM5α restriction factor, and a HIV TAR decoy. This strategy has been shown to prevent infection in vitro and in vivo, and 12 PWH requiring autologous SCT for lymphoma have already received gene modified stem cells through AMC097. One participant stopped ART outside study protocol following SCT and experienced post-treatment control. Whereas the primary endpoints of the study are to evaluate the safety of such an approach, support is urgently needed to perform in- depth HIV reservoir analyses and to implement assays to determine if gene modified cells become infected following transplantation with or without analytical treatment interruption. We will: (1) test the hypothesis that autologous SCT with gene modified stem cells simultaneously targeting different stages of the HIV-1 replication cycle will lead to blood and gut tissue expansion and maintenance of a transduced CD4+ T and other immune cells resistant to HIV-1 infection; (2) test the hypothesis that SCT with gene modified stem cells will reduce the size of the HIV-1 reservoir and residual HIV-1 transcriptional activity, and lead to post-treatment HIV control following withdrawal of ART, and (3) determine if gene modified cells become infected prior to and following cessation of ART a novel duplexed single-cell-droplet (scdPCR) assay with the ability to simultaneously detect cellular HIV-1 DNA or RNA and the integrated lentiviral vector or chimeric TRIM5α transcriptional activity.

概述/摘要：使用抗HIV感染的自体基因修饰细胞来减少HIV感染。 病毒库的大小和延迟或防止艾滋病毒复发是艾滋病毒治疗科学的前沿。然而，在这方面， 目前许多基因修饰方法仅集中于降低造血干细胞上的CCR 5表达， 细胞或成熟的CD 4 T细胞。这些方法可能对艾滋病毒感染者（PWH）的影响有限， 病毒能够使用其他辅助受体进入，并且仅提供单层保护以防止感染， vivo.因此，AMC #097研究，“由人介导的艾滋病毒干细胞基因治疗的I期研究” Lentivector转导的预先选择的CD 34+细胞：艾滋病患者联盟的试验”， 实施联合收割机，将多个抗HIV基因组合到单个慢病毒载体中，该慢病毒载体设计用于阻断HIV-1 在HIV-1生命周期的不同阶段感染，提供对HIV-1感染的强整合前抑制 使用慢病毒载体，所述慢病毒载体包括CCR 5 shRNA、嵌合人-macaqueTRIM 5 α限制性因子和 HIV TAR诱饵这种策略已被证明可以预防体外和体内感染，12例PWH需要 用于淋巴瘤的自体SCT已经通过AMC 097接受了基因修饰的干细胞。一位与会者 SCT后在研究方案之外停止ART，并经历了治疗后控制。而初级 该研究的终点是评估这种方法的安全性，迫切需要支持，以执行- 深入的HIV储库分析，并实施检测以确定基因修饰的细胞是否被感染 在移植后中断或不中断分析治疗。我们将：（1）测试假设， 用基因修饰的干细胞同时靶向HIV-1复制的不同阶段的自体SCT 循环将导致血液和肠道组织扩张，并维持转导的CD 4 + T和其他免疫应答。 对HIV-1感染有抵抗力的细胞;（2）检验用基因修饰的干细胞进行SCT将减少 HIV-1储存库的大小和残留的HIV-1转录活性，并导致治疗后的HIV控制 在停止ART之后，和（3）确定基因修饰的细胞在ART之前和之后是否被感染， 停止ART一种新型的单细胞滴（scdPCR）检测方法，能够同时检测 细胞HIV-1 DNA或RNA和整合的慢病毒载体或嵌合TRIM 5 α转录活性。