Genetic imprints of therapeutic Ad26/MVA mosaic vaccine in rebound HIV-1 genome from acutely treated individuals

摘要 由于HIV-1传播后不久就建立了持久的宿主，终身抗逆转录病毒治疗 是维持HIV-1感染者病毒载量抑制所必需的。发展 制定能够诱导长期、无抗逆转录病毒药物缓解的策略是公共卫生的高度优先事项。 一个重要的策略是治疗性艾滋病毒疫苗。虽然迄今为止，大多数人 治疗性疫苗未能显示出临床益处，一些疫苗显示出疫苗的证据 疗效作为延迟反弹或降低病毒载量的设定点。这提供了 如果能开发出优化的疫苗策略，就有希望实现长期缓解。 拟议的研究利用了一个非常独特的机会来采用新的测序 了解病毒进化模式以响应治疗的技术 一种有希望的Ad26.Mos/MVA疫苗接种方案在急性中的应用 在RV405中接受分析治疗中断(ATI)的接受治疗的个人 学习。这将是第一个在随机安慰剂环境下进行的HIV-1基因研究。 对照治疗性疫苗试验。初步分析表明，成功引出了 所有RV405疫苗接受者的免疫反应和对病毒的轻微延迟 疫苗臂中的装载量反弹。我们的中心假设是免疫反应 AD26/MVA疫苗的接种将对复制的病毒施加选择压力 在反弹过程中，这将在反弹的病毒基因组中留下“基因印记”。两者都有 T/F病毒的遗传背景及其对病毒应答的进化轨迹 疫苗引起的免疫压力将与疫苗结果相关。我们 提出以下具体目标： 目的1：比较抗逆转录病毒治疗前和反弹病毒群体的基因组成 并在反弹病毒基因组中识别与疫苗相关的基因印记。 目的2：确定T/F和T/F疫苗结果的病毒遗传相关性 反弹的病毒基因组。 我们的长期目标是将有关艾滋病毒脆弱性的知识转化为优化未来 疫苗战略，以实现艾滋病毒缓解和根除的目标。

Summary Due to the persistent reservoir established soon after HIV-1 transmission, life-long ART is required to maintain viral load suppression in HIV-1 infected individuals. Development of strategies able to induce long-term, ART-free remission is a high public health priority. One important strategy is therapeutic HIV vaccine. Although to date, majority of therapeutic vaccines failed to show clinical benefit, some showed evidence of vaccine efficacy as a delayed time to rebound or decreased viral load set point. This provides the hope to achieve a long-term remission if optimized vaccine strategies can be developed. The proposed study leverages a highly unique opportunity to employ novel sequencing technologies to understand viral evolutionary patterns in response to therapeutic vaccination in a promising Ad26.Mos/MVA.Mos vaccine regimen amongst acutely treated individuals who underwent analytical treatment interruption (ATI) in the RV405 study. This will be the first HIV-1 genetic study in the setting of a randomized, placebo- controlled therapeutic vaccine trial. Preliminary analysis showed successfully elicited immune responses in all RV405 vaccine recipients and a slightly delayed time to viral load rebound in the vaccine arm. Our central hypothesis is that the immune responses elicited by Ad26/MVA vaccination will exert selection pressures on the replicating viruses during rebound, which will leave “genetic imprints” in the rebound viral genomes. Both the genetic background of the T/F virus and its evolutionary trajectory in response to vaccine-induced immune pressures will correlate with the vaccine outcomes. We propose the following specific aims: Aim 1: To compare the genetic compositions of pre-ART and rebound viral populations and to identify vaccine-related genetic imprints in rebound viral genomes. Aim 2: To identify viral genetic correlates of the vaccine outcomes in both the T/F and rebound viral genomes. Our long-term goal is to translate knowledge of HIV vulnerabilities into optimizing future vaccine strategies towards the goal of HIV remission and eradication.