Optimizing HIV-specific T-cell responses by therapeutic vaccination

项目总结/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感染仍然是一个严重的问题。 慢性疾病给患者和医疗保健系统造成了巨大的负担。此外， 很明显，长期的抗逆转录病毒疗法不会消除艾滋病毒，迫使患者终身接受所有治疗。 有害的副作用因此，努力根除艾滋病毒感染，或至少诱导病毒控制状态， 需要无药物缓解。随着病毒整合到长寿T细胞群体的宿主基因组中， 可以在潜伏状态下持续存在，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HIV精英控制者的小子集中观察到， 由于在没有ART的情况下无法检测到病毒载量，因此在大多数HIV感染者中， 控制或消除病毒库。治疗性疫苗被认为可以增强病毒特异性 免疫应答以改善宿主对病毒复制的控制并减小病毒库的大小。 然而，水库中频繁的病毒逃逸突变对这一概念提出了挑战，因此， 疫苗策略需要诱导尚未经历免疫选择的T细胞应答 压力诱导广泛细胞免疫应答的一种策略是利用生物信息学优化的HIV-1， 1“镶嵌”抗原和来自非人灵长类动物模型的临床前数据证实，这些疫苗 扩大细胞免疫宽度，并导致猴血浆中位设定点显著降低 抗逆转录病毒治疗中断后的免疫缺陷病毒（SIV）水平。因此，我们假设HIV特异性CD 4 慢性感染ART抑制个体中的CD 8和CD 8 T细胞应答可以通过治疗来优化， 用表达嵌合Gag/Pol和Env表位的基于ad 26/MVA载体的疫苗接种，以1）靶向 新的和/或次显性表位，2）交叉反应性T细胞受体（TCR）克隆型，3）将导致 在增强抗病毒T细胞对储库病毒的效力。因此，我们建议1）精细映射T细胞 疫苗接种前后的反应，2）应用最先进的测序技术来确定变化 和3）确定抗HIV-1区段的抗病毒CD 8 T细胞活性 储库病毒总的来说，在这个建议中，我们的目标是系统地确定一个尖端的能力， 诱导功能增强和抗储库T细胞应答的疫苗方案，目的是告知 合理设计针对功能性HIV治愈策略优化的治疗性疫苗。

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.