Reversal of HIV Cognitive Disease in Mice Employing Broadly Specific T Cell Vaccines

使用广泛特异性 T 细胞疫苗逆转小鼠的 HIV 认知疾病

• 批准号: 9924841
• 负责人: MARY Jane POTASH
• 金额: $ 8.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924841
• 关键词: Adenovirus Vector; Adenoviruses; Affect; Applications Grants; Area; Behavioral; Biological Assay; Biology; Brain; Brain Diseases; CD8-Positive T-Lymphocytes; Cells; Chronic; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Collaborations; DNA; DNA biosynthesis; Defect; Development; Disease; Epitopes; Flow Cytometry; Funding; Goals; HIV; Human; Immune system; Immunization; Immunologic Surveillance; Immunologics; Impairment; Infection; Innate Immune Response; Insulin; Learning; Letters; Memory; Methods; Mission; Modeling; Mosaicism; Mus; Myeloid Cells; National Institute of Neurological Disorders and Stroke; Neurocognitive Deficit; Neurons; Patients; Peptides; Pilot Projects; Poxviridae; Preclinical Testing; Proteins; Radial; Recovery; Refractory; Reporting; Request for Applications; Research; Route; Surface; T cell response; T-Lymphocyte; Testing; Time; Tissues; Vaccine Therapy; Vaccines; Vaccinia virus; Viral; Virus; adaptive immune response; antiretroviral therapy; arm; base; behavior test; cytokine; efficacy testing; experimental study; immune system function; macrophage; mild neurocognitive impairment; mind control; mouse model; novel; novel strategies; prevent; programs; research clinical testing; response; success; therapeutic evaluation; therapy development; tool; vector vaccine; water maze

PROJECT SUMMARY This R03 application requests funds for research in an area of high relevance to the mission of the NINDS; specifically, to use an existing mouse model of HIV-associated neurocognitive impairment (HIV-NCI) for preclinical testing of therapeutic vaccination to reverse the disease employing T cell vaccines against conserved determinants present on HIV worldwide. People living with HIV due to successful combination antiretroviral therapy CART have low HIV burdens, functioning immune systems, and are relatively healthy, but about half of them develop chronic HIV-NCI that is not currently treatable. The disease is believed to be driven by myeloid cell reservoirs of HIV that defy the CART- restored anti-HIV immune surveillance. This small grant application proposes to use our well- established model of HIV-NCI in conventional mice infected by chimeric HIV, EcoHIV, to test therapeutic vaccination against the disease using state of the art broadly specific mosaic Gag-Pol T cell vaccines created by our collaborator Dr. Tomas Hanke. As recently reported, HIV-NCI in EcoHIV infected mice can be reversed by intranasal insulin treatment, suggesting that neurons relevant to cognition remain viable despite HIV insult, consistent with spontaneous cognitive improvement seen in some patients with NCI. As shown in Preliminary Results, innate immune stimulation also reverses HIV NCI in infected mice, as well as reduces virus burdens, suggesting that infected cells can directly be controlled through immunological routes. Dr Hanke's previous T cell vaccines protect mice from EcoHIV infection, as shown in our collaboration. Importantly, the vaccines to be employed, presented as Gag-Pol mosaic constructs, carry globally conserved determinants that are also associated with low virus burden in human beings and have entered clinical evaluation. The overall goal of this proposal is to test the novel mosaic vaccines for their ability to affect virus burden and behavioral change in EcoHIV-infected mice with NCI. The Aim is a) to optimize responses to DNA-, replication-deficient poxvirus MVA-, and replication-deficient adenovirus-vectored vaccines for reduction of virus burden and recovery of learning and memory in HIV-NCI mice; and b) to begin to identify antigenic determinants recognized by T cells associated with protective responses. Methods include immunization routes, assessment of virus burden in various tissues, memory and learning tests, and assay of peptide responses of CD4 and CD8 T cells. This pilot study will form the basis of a comprehensive study to employ therapeutic vaccination to boost adaptive immune responses to globally shared HIV determinants to reverse or prevent the development of HIV cognitive disease in infected people.

项目摘要 该R03申请要求在与任务高度相关的领域进行研究 Ninds；具体而言，使用现有的与HIV相关神经认知障碍的鼠标模型 （HIV-NCI）用于治疗疫苗接种的临床前测试，以逆转使用T细胞的疾病 全球艾滋病毒上存在的疫苗反对保守的决定因素。由于艾滋病毒而受艾滋病毒 成功组合抗逆转录病毒疗法的艾滋病毒负担较低，可免疫功能 系统，并且相对健康，但是其中大约一半发展了慢性HIV-NCI目前尚未 可以治疗。据信这种疾病是由艾滋病毒的髓样细胞储存剂驱动的，这无视手推车 恢复的抗HIV免疫监测。这个小的赠款申请建议使用我们的福祉 在感染了嵌合HIV的常规小鼠中，已建立的HIV-NCI模型，以测试 使用艺术状态对疾病的治疗性疫苗接种，广泛特异 由我们的合作者托马斯·汉克（Tomas Hanke）创建的疫苗。正如最近报道的那样，ecohiv中的HIV-NCI 受感染的小鼠可以通过鼻内胰岛素治疗来逆转，这表明神经元与 尽管艾滋病毒侮辱，但认知仍然可行，与自发的认知改善一致 一些NCI患者。如初步结果所示，先天免疫刺激还逆转了HIV 受感染小鼠的NCI，以及减轻病毒负担，表明感染细胞可以直接 通过免疫路线控制。汉克博士以前的T细胞疫苗可保护小鼠免受 Ecohiv感染，如我们的合作所示。重要的是，要使用的疫苗 作为GAG-POL镶嵌构建体，携带全球保守的决定因素，也与低相关 人类中的病毒负担，已经进入了临床评估。该提议的总体目标是 测试新颖的镶嵌疫苗，以影响病毒负担和行为改变的能力 用NCI感染生态的小鼠。目的是a）优化对DNA-的响应 痘病毒MVA-和复制缺陷的腺病毒载体疫苗可减轻病毒负担和 HIV-NCI小鼠的学习和记忆的恢复； b）开始识别抗原决定因素 由与保护性反应相关的T细胞识别。方法包括免疫路线， 评估各种组织中的病毒负担，记忆和学习测试以及肽的测定 CD4和CD8 T细胞的反应。这项试验研究将构成一项全面研究的基础 采用治疗性疫苗接种来增强对全球艾滋病毒的适应性免疫反应 扭转或防止感染人中艾滋病毒认知疾病的决定因素。