An AAV Approach to Treating HIV

治疗 HIV 的 AAV 方法

基本信息

批准号：
9204200
负责人：
Matthew Ryan Gardner
金额：
$ 5.61万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204200
关键词：
Address Affinity Animals Anti-Retroviral Agents Antibodies Antibody Therapy Binding Sites Biological Assay CCR5 gene CXCR4 gene Cell surface Data Dependovirus Detection Disease Dose Fellowship Gene Transduction Agent Goals HIV HIV Entry Inhibitors HIV vaccine HIV-1 HIV-2 Human Immune response Individual Infection Injection of therapeutic agent Inorganic Sulfates Interferons Intravenous Macaca Macaca mulatta Measurable MicroRNAs Pathway interactions Pharmacotherapy Positioning Attribute Principal Investigator Production Proteins Publishing Regulation Research Research Training Resistance SIV Safety Testing Time Transgenes Unspecified or Sulfate Ion Sulfates Viral Viral Load result Viremia Virus Work World Health Organization adeno-associated viral vector antiretroviral therapy base deep sequencing gene therapy humanized mouse immunogenic improved in vitro Assay in vivo inhibitor/antagonist neutralizing antibody peptidomimetics receptor research study response simian human immunodeficiency virus transgene expression viral RNA

项目摘要

PROJECT SUMMARY We have recently published our research that characterizes eCD4-Ig. eCD4-Ig is an antibody-like HIV entry inhibitor that fuses a sulfated CCR5-mimetic peptide to the C-terminus of CD4-Ig. Based on neutralization assay data, eCD4-Ig is broader than and equally potent as some of the best described HIV-1 broadly neutralizing antibodies to date. eCD4-Ig neutralized all isolates tested including 38 HIV-1 isolates resistant to 3BNC117 or NIH45-46, HIV-2, SIVmac239, SIVmac251, and isolates that use CXCR4 as their coreceptor. The addition of the CCR5-mimetic peptide allowed eCD4-Ig to have higher affinity for cell surface-expressed HIV-1 Env and also limited viral enhancement caused by sub-neutralizing levels of CD4-Ig. Using adeno-associated virus (AAV) vectors, we have shown that a rhesus form of eCD4-Ig can be expressed in four rhesus macaques for over one year with no harm to the animals. The rh- eCD4-Ig protein titers were at levels that protected all four macaques from multiple SHIV-AD8 challenges up to 16-times the AID50 (Animal Infectious Dose 50). We did observe a measurable anti- transgene response to the expressed rh-eCD4-Ig protein, but the response was not near the levels seen against AAV-delivered HIV-1 antibodies. Yet, even a relatively modest immune response to the delivered transgene can limit the inhibitor’s efficacy in vivo. With these encouraging data, this proposal seeks to answer two main questions: (1) Can AAV-expressed eCD4-Ig be used as a therapy to maintain viral suppression in SHIV infected macaques? (2) Can interferon-induced miRNAs regulate transgene expression from AAV vectors to limit the host immune response to the transgene? With the primary goal of using eCD4-Ig as an alternative to antiretroviral therapies, answering these two questions will continue to build on the safety and efficacy of AAV-delivered eCD4-Ig as well as realizing the complete potential of AAV vectors used for gene therapy.

项目摘要我们最近发表了我们的研究，该研究角色ecd4-ig。 ECD4-Ig是一种类似抗体的HIV 将硫化CCR5模拟肽融合到CD4-Ig的C末端的进入抑制剂。基于协商测定数据，ECD4-Ig比一些最佳描述的eCD4-Ig更广泛，并且具有同样的潜力 HIV-1迄今为止广泛中和抗体。 ECD4-Ig中和所有测试的分离株，包括38 HIV-1 抗抗对3BNC117或NIH45-46，HIV-2，SIVMAC239，SIVMAC251的分离物，以及使用CXCR4作为他们的cocector。添加CCR5模拟肽使ECD4-Ig具有更高的亲和力细胞表面表达的HIV-1 Env，也限制了由亚中和水平引起的病毒增强 CD4-ig。使用腺相关病毒（AAV）载体，我们已经表明了Ecd4-ig的恒河猴形式可以在四个恒河猕猴中表达一年以上，对动物没有任何伤害。 Rh- ECD4-Ig蛋白滴度处于保护所有四个猕猴免受多个SHIV-AD8的水平挑战长达16倍的AID50（动物感染剂量50）。我们确实观察到了可测量的抗转基因对表达的RH-ECD4-Ig蛋白的反应，但反应不接近水平请参阅反对递送的HIV-1抗体。然而，即使是相对适度的免疫反应传递的转换可以限制抑制剂在体内的效率。有了这些令人鼓舞的数据，该提议试图回答两个主要问题：（1）可以将表达AAV表达的ECD4-Ig用作疗法在SHIV感染的猕猴中保持病毒抑制？（2）可以干扰诱导的miRNA调节从AAV矢量的转基因表达限制了宿主免疫反应对转换的反应？与使用ECD4-Ig作为抗逆转录病毒疗法的主要目标，回答这两种问题将继续以AAV递送的ECD4-Ig的安全性和效率为基础，并实现用于基因治疗的AAV载体的完全潜力。