Optimizing HIV-specific T-cell responses by therapeutic vaccination

通过治疗性疫苗接种优化 HIV 特异性 T 细胞反应

基本信息

批准号：
10062472
负责人：
Boris Dominik Juelg
金额：
$ 70.68万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-17 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062472
关键词：
AIDS prevention Adenoviruses Anti-Infective Agents Antigens Antiviral Agents Bioinformatics CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Count Cells Characteristics Chronic Chronic Disease Chronic Phase Cytotoxic T-Lymphocytes Data Disease remission Epitopes Future Generations Genome Goals HIV HIV Infections HIV vaccine HIV-1 Healthcare Systems Immune Immune response Immunosuppression Individual Infection Interruption Leukapheresis Life Macaca mulatta Maps Mediating Memory Modeling Modernization Modification Modified Vaccinia Virus Ankara Mosaicism Mutation Nature Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Plasma Population Predisposition Prevention strategy Procedures Regimen SIV T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Technology Testing Thailand Therapeutic Vaccination Vaccine Therapy Vaccines Variant Viral Viral Load result Viral reservoir Virus Virus Replication antiretroviral therapy base cohort cross reactivity design env Gene Products experience immunogenic improved insight latent HIV reservoir nonhuman primate novel novel vaccines phase 1 study pre-clinical pressure response side effect success therapeutic vaccine vaccination outcome vaccine candidate vaccine trial vaccine-induced immunity vector vector-based vaccine viral rebound

项目摘要

PROJECT SUMMARY/ABSTRACT Despite the success of modern anti-retroviral therapy (ART) in limiting HIV replication, HIV infection remains a chronic disease creating a substantial burden for both patients and the healthcare system. Moreover, it has become evident that long-term ART will not eliminate HIV, forcing patients to stay on life-long therapy with all its deleterious side effects. Thus, efforts to eradicate HIV infection, or at least induce a state of viral control and drug-free remission are needed. As the virus integrates into the host genome of long-lived T cell populations, it can persist in a latent state creating the viral reservoir and while HIV-1-specific cellular immune responses can partially control virus replication, e.g. as observed in the small subset of HIV elite controllers that have undetectable viral loads in the absence of ART, they have failed in the majority of HIV infected individuals to control or eliminate the viral reservoir. Therapeutic vaccines have been considered to augment virus-specific immune responses to improve host control of virus replication and reduce the size of the viral reservoir. However, frequent viral escape mutations in the reservoir have challenged this concept and thus a therapeutic vaccine strategy will need to induce T-cell responses that have not already experienced immune selection pressure. One strategy to induce broad cellular immune responses is to utilize bioinformatically optimized HIV- 1 “mosaic” antigens and preclinical data from the non-human primate model confirm that these vaccines expanded cellular immune breadth and result in a significant reduction of median setpoint plasma simian immunodeficiency virus (SIV) levels following ART interruption. Thus, we hypothesize that HIV-specific CD4 and CD8 T-cell responses in chronically infected ART-suppressed individuals can be optimized via therapeutic vaccination with an ad26/MVA vector based vaccine expressing mosaic Gag/Pol and Env epitopes to 1) target novel and/or subdominant epitopes, with 2) cross-reactive T-cell receptor (TCR) clonotypes which 3) will result in enhanced antiviral T-cell efficacy against reservoir viruses. We therefore propose 1) to fine map T-cell responses pre- and post-vaccination, 2) to apply state-of-the-art sequencing technology to determine changes in TCR-repertoire and function and 3) to determine antiviral CD8 T-cell activity against segments of HIV-1 reservoir viruses. Collectively, in this proposal we aim to systematically determine the ability of a cutting edge vaccine regimen to induce functionally enhanced and anti-reservoir T-cell responses with the goal to inform the rational design of therapeutic vaccines optimized for functional HIV cure strategies.

项目概要/摘要尽管现代抗逆转录病毒疗法 (ART) 在限制 HIV 复制方面取得了成功，但 HIV 感染仍然是一个此外，慢性病给患者和医疗保健系统造成了沉重负担。很明显，长期抗逆转录病毒治疗并不能消除艾滋病毒，迫使患者接受终生治疗因此，努力根除艾滋病毒感染，或至少诱导病毒控制和恢复状态。当病毒整合到长寿 T 细胞群的宿主基因组中时，需要无药物缓解。可以持续处于潜伏状态，形成病毒库，而 HIV-1 特异性细胞免疫反应可以部分控制病毒复制，例如在一小部分艾滋病毒精英控制者中观察到在没有抗逆转录病毒治疗的情况下，病毒载量无法检测到，因此在大多数艾滋病毒感染者中，它们未能检测到病毒载量控制或消除病毒库已被认为可以增强病毒特异性。免疫反应以改善宿主对病毒复制的控制并减少病毒库的大小。然而，病毒储存库中频繁发生的病毒逃逸突变对这一概念提出了挑战，因此也挑战了一种治疗方法。疫苗策略需要诱导尚未经历免疫选择的 T 细胞反应诱导广泛细胞免疫反应的一种策略是利用生物信息优化的 HIV- 1 来自非人类灵长类动物模型的“马赛克”抗原和临床前数据证实这些疫苗扩大细胞免疫广度并导致中位点血浆猿显着降低 ART 中断后免疫缺陷病毒 (SIV) 水平因此，我们面临着 HIV 特异性 CD4。慢性感染 ART 抑制个体的 CD8 T 细胞反应可以通过治疗得到优化使用基于 ad26/MVA 载体的疫苗进行疫苗接种，该疫苗表达嵌合 Gag/Pol 和 Env 表位至 1) 目标新的和/或次优势表位，具有 2) 交叉反应性 T 细胞受体 (TCR) 克隆型，这 3) 将产生因此，我们建议 1) 精细绘制 T 细胞图谱。疫苗接种前和疫苗后的反应，2) 应用最先进的测序技术来确定变化 TCR 库和功能，以及 3) 确定针对 HIV-1 片段的抗病毒 CD8 T 细胞活性总的来说，在本提案中，我们的目标是系统地确定尖端病毒的能力。诱导功能增强和抗储存 T 细胞反应的疫苗方案，目的是告知合理设计针对功能性艾滋病毒治疗策略进行优化的治疗性疫苗。