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

• 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
• 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

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.

项目摘要/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感染仍然是一种 慢性疾病为患者和医疗保健系统造成了大量灼伤。而且，它有 成为长期艺术不会消除艾滋病毒的证据，迫使患者与所有人保持终身治疗 它有害的副作用。那是放射性艾滋病毒感染的努力，或至少诱导病毒控制状态和 需要无药缓解。随着病毒整合到长寿命T细胞种群的宿主基因组中， 可以在潜在状态下持续创建病毒储存剂，而HIV-1特异性的细胞免疫调查会可以 部分控制病毒复制，例如如在艾滋病毒精英控制器的一小部分中观察到的那样 在没有艺术的情况下，无法检测到的病毒载荷失败了，大多数艾滋病毒感染者都失败了 控制或消除病毒库。已经认为治疗疫苗可以增加病毒特异性 免疫反应以改善病毒复制的宿主控制并减少病毒储存剂的大小。 但是，水库中经常病毒逃生突变已挑战了这一概念，因此是一种治疗 疫苗策略将需要诱导尚未经历免疫选择的T细胞反应 压力。诱导广泛细胞免疫复杂的一种策略是利用生物信息优化的HIV- 1非人类私人模型的“马赛克”抗原和临床前数据证实了这些疫苗 扩展的细胞免疫读物，并显着减少中位设定点等离子体猿猴 ART中断后的免疫缺陷病毒（SIV）水平。那我们假设HIV特异性CD4 可以通过治疗优化慢性感染艺术抑制的个体中的CD8 T细胞反应 带有AD26/MVA载体的疫苗，基于镶嵌的疫苗，表达镶嵌性GAG/POL和ENV表位为1）目标 新型和/或亚尺寸表位，带有2）交叉反应性T细胞受体（TCR）clonotypes，其中3）将导致 在增强针对储层病毒的抗病毒T细胞效率中。因此，我们建议1）罚款T细胞t-cell 疫苗发生前后的响应，2）应用最先进的测序技术来确定变化 在TCR-Repertoire和功能以及3）确定针对HIV-1段的抗病毒CD8 T细胞活性 水库病毒。总的来说，在此提案中，我们旨在系统地确定尖端的能力 疫苗方案诱导功能增强和抗渗透性T细胞反应，以告知该目标 为功能性HIV治疗策略优化的热疫苗的合理设计。