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

基本信息

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
项目类别：
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

项目摘要

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.

摘要/摘要：使用抗 HIV 感染的自体基因修饰细胞来减少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。目前许多基因修饰方法仅专注于减少造血干上的 CCR5 表达这些方法对患有 HIV 的人 (PWH) 的影响可能有限。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因此，AMC #097 研究“干细胞基因治疗 HIV 介导的 I 期研究”。慢载体转导、预选 CD34+ 细胞：艾滋病恶性肿瘤联盟的一项试验” 将多个抗 HIV 基因组合到一个旨在阻断 HIV-1 的慢病毒载体中 HIV-1 生命周期不同阶段的感染，对 HIV-1 感染提供强大的预整合抑制使用包含 CCR5 shRNA、嵌合人-猕猴 TRIM5α 限制因子的慢病毒载体，以及 HIV TAR 诱饵已被证明可以在体外和体内预防感染，并且需要 12 个 PWH。淋巴瘤自体 SCT 已通过 AMC097 接受基因修饰干细胞。在 SCT 后停止研究方案外的 ART 并经历治疗后控制。该研究的终点是评估这种方法的安全性，迫切需要支持来执行深度 HIV 储存库分析并实施检测以确定基因修饰细胞是否被感染在有或没有分析治疗中断的移植后，我们将：（1）检验以下假设：使用基因修饰干细胞的自体 SCT 同时针对 HIV-1 复制的不同阶段循环将导致血液和肠道组织扩张并维持转导的 CD4+ T 和其他免疫抵抗 HIV-1 感染的细胞；(2) 检验基因修饰干细胞的 SCT 将减少 HIV-1 感染的假设 HIV-1 储存库的大小和残留的 HIV-1 转录活性，并导致治疗后 HIV 控制撤回 ART 后，(3) 确定基因修饰细胞在 ART 之前和之后是否被感染停止 ART 一种新型双工单细胞液滴 (scdPCR) 检测，能够同时检测细胞HIV-1 DNA或RNA以及整合的慢病毒载体或嵌合TRIM5α转录活性。