Anti-HIV Gene Delivery to Human Hematopoietic Cells

抗 HIV 基因递送至人类造血细胞

基本信息

批准号：
7923150
负责人：
Bruce Edward Torbett
金额：
$ 40.79万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7923150
关键词：
Accounting Acquired Immunodeficiency Syndrome Address Allogenic Antibodies Autologous Basic Science Biological Assay Blood Cells CCR5 gene CD34 gene CD4 Positive T Lymphocytes CXCR4 gene Capsid Cell Line Cell Transplants Cell physiology Cells Clinical Development Drug Combinations Drug resistance Engraftment Gene Delivery Gene Targeting Genes Goals Growth HIV HIV drug resistance HIV-1 Hematopoiesis Hematopoietic Hematopoietic stem cells Highly Active Antiretroviral Therapy Human Infection Investigation Lentivirus Vector Methods Modality Movement Mutation Myelogenous NOD/SCID mouse Pathway interactions Patients Peptides Pharmacotherapy Principal Investigator Probability Property Proteins RNA Refractory Research Resistance Route Site Source T cell differentiation T-Cell Development T-Lymphocyte Therapeutic Time Toxic effect Viral Viral Genes Viral Load result Viral Physiology Virus base chemokine receptor combinatorial improved insight macrophage monocyte novel programs small hairpin RNA vector viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): The goals for this proposal are to investigate toxicity and function of lentiviral vector delivered, proven gene- based HIV-1 disruption modalities in human hematopoietic stem cells (HSCs), myeloid and CD4+ T cells. It is estimated that 30-45% of AIDS patients on Highly Active Anti-Retroviral Therapy (HAART) having demonstrable virus have some form of drug resistance. Thus, the continuing emergence of drug resistant HIV-1s makes it imperative to develop therapeutics with novel mechanisms of action. We posit that by employing a combination of proven, gene-based HIV-1 disruption modalities, and the use of lentiviral vectors for delivery to CD34+ and T cells, anti-HIV-1 gene positive cells may be refractory to infection, not replicate virus efficiently, and protected cells will enrich over time. Our long-term goals are to provide basic research findings on viral and cellular gene disruption strategies that may find use for autologous T and CD34+ cell or allogenic CD34+ cell transplant sources for patients that have or are going to fail HAART. Analogous to combination drug strategies used for HAART, we are completing a lentiviral delivery vector containing multiple genes that target cellular and HIV messages and proteins, thereby disrupting viral entry, integration, viral and cellular function. Moreover, target sites have been selected that if mutations arise the resulting virus should be less fit. Our goals will be achieved by the successful completion of four highly interactive Specific Aims: 1) Complete lentiviral vectors containing multiple HIV-1 disruption genes. 2) Do anti-HIV lentiviral vectors provide protection from HIV-1 while not disrupting normal cellular function? 3) Does expression of anti-HIV genes alter human hematopoiesis and thymopoiesis? 4) Do HSCs containing anti-HIV genes give rise to myeloid and CD4+ T cells that are protected from HIV-1 challenge? When completed these studies will provide information on whether lentiviral vectors containing multiple anti- viral genes targeting HIV-1 and its cellular pathways disrupt hematopoietic function. Our findings will also provide insight into whether selected combinations of anti-viral genes confer a cell protective and selective advantage in the presence of HIV-1-infection. Lastly, it is anticipated that many of the gene disruption and lentiviral vector delivery strategies developed and validated during our studies will be applicable for other basic research and clinical uses. Project Narrative: It is estimated that 30-45% of AIDS patients on Highly Active Anti-Retroviral Therapy (HAART) having demonstrable virus have some form of drug resistance. Thus, the continuing emergence of drug resistant HIV-1s requires new therapies for treatment. Our long-term goals are to provide basic research findings on gene delivery of viral and cellular anti-HIV-1 strategies that make blood cells resistant to HIV-1 infection and reduce growth of HIV-1. These new therapies may be utilized for T cell and CD34+ cell transplant sources for patients that have or are going to fail HAART.

描述（由申请人提供）：该提案的目标是研究人类造血干细胞（HSC），髓样和CD4+ T细胞中传递的慢病毒载体的毒性和功能。据估计，具有可证明病毒的高度活性抗逆转录病毒疗法（HAART）的AIDS患者中有30-45％具有某种形式的耐药性。因此，抗药性HIV-1的持续出现使得必须使用新颖的作用机理开发治疗剂。我们认为，通过结合经过验证的基于基因的HIV-1破坏方式，以及使用慢病毒载体将其递送到CD34+和T细胞中，抗HIV-1基因阳性细胞可能会对感染产生顽固性，而不是有效地复制病毒，并且会随着时间的推移而富裕。我们的长期目标是提供有关病毒和细胞基因破坏策略的基础研究结果，这些发现可能会发现自体T和CD34+细胞或同种异体CD34+细胞移植源，以使HAART失败或将使HAART失败。类似于HAART使用的组合药物策略，我们正在完成一个慢病毒递送载体，该载体载体包含靶向细胞和HIV信息和蛋白质的多个基因，从而破坏了病毒入口，整合，病毒和细胞功能。此外，已经选择了目标位点，如果发生突变，则将导致的病毒较小。我们的目标将通过成功完成四个高度互动特定的目的来实现：1）包含多个HIV-1破坏基因的完整慢病毒向量。 2）抗HIV慢病毒载体是否可以保护HIV-1，而不会破坏正常的细胞功能？ 3）抗HIV基因的表达是否改变了人类造血和胸腺胞菌？ 4）含有抗HIV基因的HSC是否会引起受HIV-1挑战的髓样和CD4+ T细胞？完成后，这些研究将提供有关含有多种靶向HIV-1及其细胞途径的多种抗病毒基因的慢病毒载体的信息。我们的发现还将洞悉抗病毒基因的选定组合是否在存在HIV-1感染的情况下赋予细胞保护和选择性优势。最后，可以预料，在我们的研究期间开发和验证的许多基因破坏和慢病毒载体输送策略将适用于其他基础研究和临床用途。项目叙述：据估计，有30-45％的艾滋病患者接受具有某种形式的耐药性的高度活性抗逆转录病毒疗法（HAART）。因此，耐药性HIV-1的持续出现需要新的治疗疗法。我们的长期目标是提供有关病毒和细胞抗HIV-1策略的基因递送的基础研究结果，这些策略使血细胞具有抗HIV-1感染并降低HIV-1的生长。这些新疗法可能用于T细胞和CD34+细胞移植源，用于患有或将失败HAART的患者。