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

项目概要 此 R03 申请要求为与使命高度相关的领域的研究提供资金 NINDS；具体来说，使用现有的 HIV 相关神经认知障碍小鼠模型 (HIV-NCI) 用于利用 T 细胞逆转疾病的治疗性疫苗接种的临床前测试 针对全世界艾滋病毒保守决定因素的疫苗。艾滋病毒感染者由于 成功的联合抗逆转录病毒疗法 CART 具有低 HIV 负担、功能强大的免疫功能 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 可治疗的。这种疾病被认为是由 HIV 骨髓细胞储存库驱动的，这种储存库违背了 CART- 恢复了抗艾滋病毒免疫监视。这笔小额赠款申请建议使用我们良好的 在感染嵌合HIV、EcoHIV的常规小鼠中建立HIV-NCI模型，以进行测试 使用最先进的广泛特异性嵌合 Gag-Pol T 细胞对疾病进行治疗性疫苗接种 我们的合作者托马斯·汉克博士研制的疫苗。据最近报道，EcoHIV 中的 HIV-NCI 受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 损伤，认知仍然可行，这与在 一些 NCI 患者。如初步结果所示，先天免疫刺激也能逆转 HIV 受感染小鼠中的 NCI 也减少了病毒负担，这表明受感染的细胞可以直接被 通过免疫途径控制。汉克博士之前的 T 细胞疫苗可以保护小鼠免受 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 镶嵌结构，携带全球保守的决定因素，这些决定因素也与低 人类的病毒负荷并已进入临床评估。该提案的总体目标是 测试新型嵌合疫苗影响病毒负荷和行为改变的能力 感染 EcoHIV 且患有 NCI 的小鼠。目标是 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，用于减少病毒负荷和 HIV-NCI 小鼠的学习和记忆恢复； b) 开始鉴定抗原决定簇 被与保护性反应相关的 T 细胞识别。方法包括免疫途径、 评估各种组织中的病毒负荷、记忆和学习测试以及肽测定 CD4 和 CD8 T 细胞的反应。这项试点研究将构成全面研究的基础 采用治疗性疫苗接种来增强对全球共享艾滋病毒的适应性免疫反应 逆转或预防感染者发生艾滋病毒认知疾病的决定因素。

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.