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

项目摘要 本R 03申请要求在与以下使命高度相关的领域进行研究 NINDS;具体而言，使用现有的HIV相关神经认知障碍小鼠模型 （HIV-NCI）用于治疗性疫苗接种的临床前测试，以使用T细胞逆转疾病 针对全世界艾滋病毒上保守决定簇的疫苗。艾滋病毒感染者， 成功联合抗逆转录病毒疗法CART具有较低的HIV负担， 系统，并且相对健康，但其中约一半发展为目前尚未发现的慢性HIV-NCI 可以治疗的这种疾病被认为是由HIV的骨髓细胞库驱动的，这些细胞库无视CART- 恢复了抗艾滋病毒免疫监视。这份小额赠款申请建议使用我们的良好- 在嵌合HIV，EcoHIV感染的常规小鼠中建立HIV-NCI模型，以测试 使用现有技术的广泛特异性嵌合Gag-Pol T细胞的针对疾病的治疗性疫苗接种 我们的合作者托马斯·汉克博士发明的疫苗正如最近报道的那样，EcoHIV中的HIV-NCI 感染的小鼠可以通过鼻内胰岛素治疗逆转，这表明与 尽管受到HIV的伤害，认知能力仍然存在，这与在 一些NCI患者。如初步结果所示，先天免疫刺激也可逆转HIV NCI在受感染小鼠中的作用，以及减少病毒负荷，表明受感染的细胞可以直接被感染。 通过免疫途径控制。汉克博士以前的T细胞疫苗保护小鼠免受 EcoHIV感染，正如我们的合作所示。重要的是，要使用的疫苗，提出 作为Gag-Pol嵌合构建体，携带全局保守的决定簇，这些决定簇也与低表达相关。 病毒负荷，并已进入临床评价。本提案的总体目标是 为了测试新型嵌合疫苗对病毒负荷和行为改变的影响， 用NCI感染EcoHIV的小鼠。目的是a）优化对DNA-、复制缺陷型 痘病毒MVA和复制缺陷型腺病毒载体疫苗，用于减少病毒负荷， HIV-NCI小鼠学习和记忆的恢复;和B）开始鉴定抗原决定簇 与保护性反应相关的T细胞识别。方法包括免疫途径， 各种组织中病毒负荷的评估、记忆和学习测试以及肽的测定 CD 4和CD 8 T细胞的反应。这项试验性研究将成为全面研究的基础， 采用治疗性疫苗接种来增强对全球共享的艾滋病毒的适应性免疫反应 逆转或预防感染者艾滋病毒认知疾病发展的决定因素。

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.