Dendritic Cell Vaccine for Controlling the Latent Reservoir

用于控制潜伏库的树突状细胞疫苗

• 批准号: 9180684
• 负责人: HANS-PETER KIEM
• 金额: $ 21.77万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-01-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180684
• 关键词: Address; Amino Acid Motifs; Anti-Retroviral Agents; Antigen Presentation; Antigens; Apoptosis; Autologous; Blood; Bone Marrow; CD40 Ligand; Cells; Clinical Trials; Collaborations; Cytolysis; Dendritic Cell Vaccine; Dendritic Cells; Development; Epitopes; Family suidae; Foundations; Genes; Goals; HIV; HIV-1; HIV-1 vaccine; HIV-2; Highly Active Antiretroviral Therapy; Human; Immune response; Immune system; Immunization; Individual; Infection; Injectable; Interruption; Lentivirus Vector; Life; Liver; Macaca; Methods; Modeling; Mosaicism; Mus; Myeloid Cells; Patients; Persons; Pharmaceutical Preparations; Phase; Pilot Projects; Proteins; Proviruses; Research; Research Institute; Role; SIV; T cell response; T-Lymphocyte; TNFSF5 gene; Tail; Testing; Therapeutic; Thymus Gland; Vaccines; Viral load measurement; Viremia; Virus; Virus Replication; Withholding Treatment; anticancer research; antiretroviral therapy; base; humanized mouse; immune activation; in vivo; mouse model; nonhuman primate; prevent; public health relevance; purge; response; success; therapeutic vaccine; tissue culture; vaccine development; vector; vector vaccine; viral rebound

 DESCRIPTION (provided by applicant): The project will develop a dendritic cell (DC)-based therapeutic vaccine to control the latent HIV-1 reservoir. Infected individuals are subject to life long treatment with antiretroviral drugs. Cessation of treatment results in a rapid rebound of virus loads that is seeded by a long-lived reservoir of latently infected T cells. The project will develop a lentiviral-vector-based, DC-targeted HIV-1 vaccine to address this problem. The approach is a two-pronged strategy that activates provirus expression in latently infected T cells and stimulates an immune response against infected cells to target them for lysis and diminish the size of the latent reservoir, with the goal of allowing patients to stop antiretroviral therapy During the R21 phase, lentiviral vectors will be generated that express HIV-1 antigens such as mosaic Gag that is optimized for CTL epitopes. The vectors will co-express CD40 ligand to increase the antigen presentation activity of the transduced DCs and stimulate antigen- specific T cell responses. The vaccine approach will then be tested in vivo using the bone marrow, liver, thymus (BLT)-humanized mouse model. HIV-infected BLT-mice on antiretroviral drugs will be injected with autologous lentiviral vector-transduced DCs to determine the fate of the transduced DCs, their role in immune activation, and their ability to disrupt the latent reservoir. BLT-mice will also be used to determine whether immunization with transduced DCs boosts HIV-specific T cell responses and facilitates control of rebound viremia following treatment interruption. The R33 phase of the project will test the lentiviral DC vaccines developed in the BLT-model in a non-human primate (NHP) pilot study using SIV-infected pig-tailed macaques. During this expanded phase, the ability of the transduced DCs to stimulate HIV-specific CTLs and target the latent reservoir will also be tested using cells from HIV-infected patients on antiretroviral therapy. The success of these studies will lay the foundation for larger scale NHP studies and clinical trials in humans.

 描述（由应用程序提供）：该项目将开发一个基于树突状细胞（DC）的热真空，以控制潜在的HIV-1储层。受感染的人受到生命的约束 抗逆转录病毒药物的长期治疗。停止治疗会导致病毒载荷的快速反弹，这是由长期寿命的潜在感染T细胞播种的。该项目将 开发基于慢病毒的基于DC靶向的HIV-1疫苗来解决此问题。 The approach is a two-pronged strategy that activates provirus expression in latently infected T cells and stimulates an immunoresponse against infected cells to target them for lysis and diminish the size of the latent reservoir, with the goal of allowing patients to stop antiretroviral therapy during the R21 phase, lentiviral vectors will be generated that express HIV-1 antigens Such as mosaic Gag that is optimized for CTL表位。向量将共表达CD40配体，以增加转移的DC的抗原表现活性并刺激抗原特异性T细胞反应。然后，将使用骨髓，肝，胸腺（BLT）人道化的小鼠模型在体内对疫苗方法进行测试。抗逆转录病毒药物的HIV感染的BLT小鼠将注入自体慢病毒载体转导的DC，以确定转移的DC的命运，它们在免疫激活中的作用以及破坏潜在储量的能力。 BLT小鼠还将用于确定翻译DC的免疫是否会增强HIV特异性T细胞反应，并促进治疗后反弹病毒血症的控制。该项目的R33阶段将测试使用SIV感染的猪尾猕猴在非人类灵长类动物（NHP）初步研究中在BLT模型中开发的慢病毒直流疫苗。在这一扩展阶段，翻译的DC刺激HIV特异性CTL并靶向潜在储层的能力也将使用抗逆转录病毒治疗的HIV感染患者的细胞进行测试。这些研究的成功将为大规模的NHP研究和人类的临床试验奠定基础。