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

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

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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：使用自体基因修饰细胞，这些细胞耐于HIV感染以减少病毒储量的大小和延迟或预防HIV复发是HIV治疗科学的最前沿。然而，许多当前的基因修饰方法仅着重于降低造血茎上的CCR5表达细胞或成熟的CD4 T细胞。这些方法可能对患有艾滋病毒（PWH）患者的影响有限病毒可以使用其他共核能进入，仅提供一层防止感染的保护体内。结果，AMC＃097研究：“一项对HIV的干细胞基因治疗的I期研究慢烟转导的，预先选择的CD34+细胞：艾滋病恶性联盟的试验，“ 实施以将多个抗HIV基因结合到单个慢病毒载体中，该基因旨在阻止HIV-1 HIV-1生命周期的不同阶段的感染提供了强烈的HIV-1感染的预融合抑制使用包括CCR5 shRNA的慢病毒载体，嵌合人-macaquetrim5α限制因子和艾滋病毒诱饵。已显示该策略可防止体外和体内感染，而12个PWH需要淋巴瘤的自体SCT已经通过AMC097接收了基因修饰的干细胞。一个参与者 SCT和经历后的治疗后控制后，停止艺术外部学习方案。而主要该研究的终点是评估这种方法的安全性，迫切需要支持以进行内部。深度艾滋病毒储量分析并实施测定，以确定基因修饰细胞是否被感染在没有分析治疗中断的情况下移植后。我们将：（1）检验以下假设。自体SCT具有基因修饰的干细胞，仅针对HIV-1复制的不同阶段周期将导致血液和肠道组织的扩张以及转移的CD4+ T和其他免疫的维持抗HIV-1感染的细胞；（2）检验以下假设，即具有基因改性干细胞的SCT将减少 HIV-1储层的大小和残留的HIV-1转录活性，并导致治疗后HIV控制撤回ART之后，（3）确定基因修饰细胞是否在之前和遵循之前感染停止艺术的一种新颖的复式单细胞滴滴（SCDPCR）测定法，具有简单检测的能力细胞HIV-1 DNA或RNA以及综合的慢病毒载体或嵌合TRIM5α转录活性。