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.

项目总结 这份R03申请申请资金，用于与联合国 NINDS；具体地说，使用现有的HIV相关神经认知障碍的小鼠模型 (HIV-NCI)用于使用T细胞进行治疗性疫苗接种以逆转疾病的临床前测试 针对全球艾滋病毒上存在的保守决定因素的疫苗。艾滋病毒携带者因 成功的联合抗逆转录病毒治疗车具有较低的艾滋病毒负担，功能免疫 系统，并且相对健康，但大约一半的人患上目前不是的慢性HIV-NCI 是可以治疗的。据信，这种疾病是由艾滋病毒的髓系细胞储备库驱动的，这些细胞库无视大车-- 恢复抗艾滋病毒免疫监测。这项小额拨款申请计划利用我们的油井- 建立HIV-NCI嵌合感染小鼠模型进行验证 使用最新的广特异性马赛克Gag-Pol T细胞进行治疗性疫苗接种 我们的合作者托马斯·汉克博士发明了疫苗。据最新报道，EcoHIV中的HIV-NCI 感染的小鼠可以通过鼻腔注射胰岛素治疗而逆转，这表明神经元与 尽管受到艾滋病毒的侮辱，认知仍然有效，这与在 一些NCI患者。初步结果显示，先天免疫刺激也能逆转艾滋病毒。 NCI在感染小鼠中的作用，以及减少病毒负担，表明受感染的细胞可以直接 通过免疫学途径控制。汉克博士之前的T细胞疫苗保护小鼠免受 EcoHIV感染，如我们的合作所示。重要的是，要使用的疫苗，提交 作为Gag-Pol镶嵌结构，携带全局保守的决定簇，这些决定簇也与Low相关 病毒在人体内的负担，已进入临床评估。这项提案的总体目标是 为了测试新型马赛克疫苗影响病毒载量和行为变化的能力 感染NCI的EcoHIV感染的小鼠。其目的是a)优化对DNA复制缺陷的反应 痘病毒MVA和复制缺陷型腺病毒载体疫苗用于减少病毒负担和 HIV-NCI小鼠学习和记忆的恢复；以及b)开始识别抗原决定簇 被与保护性反应相关的T细胞识别。方法包括免疫路线， 不同组织中病毒载量的评估、记忆和学习测试以及多肽的测定 CD4和CD8T细胞的应答。这项初步研究将构成全面研究的基础 采用治疗性疫苗接种以增强对全球共享的艾滋病毒的适应性免疫反应 逆转或预防感染者中艾滋病毒认知疾病发展的决定因素。