Role of reservoir composition and T cell immunity in HIV rebound kinetics

储库成分和 T 细胞免疫在 HIV 反弹动力学中的作用

• 批准号: 9530523
• 负责人: Peter A Barry
• 金额: $ 141.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-19 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530523
• 关键词: Affect; Aftercare; Anatomy; Anti-Retroviral Agents; Antibody Response; Bone Marrow Purging; CD4 Positive T Lymphocytes; Catalogs; Cell Count; Cells; Characteristics; Clinical Trials; Data; Dose; Drug Interactions; Epitopes; Frequencies; Generations; Genetic Transcription; HIV; HIV-1; Half-Life; Human; Immune; Immune response; Immunity; Individual; Infection; Innate Immune Response; Interleukin-10; Interruption; Kinetics; Link; Location; Longevity; Natural Immunity; Outcome; Paper; Patients; Pharmaceutical Preparations; Phenotype; Preparation; Primary Infection; Publishing; Research; Role; SIV; SIV Vaccines; Sampling; Stochastic Processes; T cell response; T-Cell Activation; T-Lymphocyte; Time; Vaccines; Variant; Vertebral column; Viral; Viral Load result; Viral Physiology; Viral reservoir; Virus; Virus Integration; Virus Replication; adaptive immunity; antiretroviral therapy; experience; human leukocyte antigen testing; human subject; integration site; neutralizing antibody; nonhuman primate; programs; response; screening; therapeutic immunization; therapy duration; tool; viral RNA; viral rebound

Most HIV-infected patients who stop taking antiretroviral drugs experience rapid viral rebound and suffer in the longer term from higher viral load and lower CD4+ T cell counts. This outcome normally occurs even when individuals have been suppressed for long periods, e.g., several decades. Thus, slow or non-existent viral rebound may occur only under restricted circumstances, including (i) early initiation of antiretroviral therapy, resulting in predominant infection of reservoir cells with shorter half-life, (ii) change in the viral reservoir under ART coverage, e.g., due to myeloablation in preparation for BMT, or (iii) change in the host's capacity for adaptive immune control over virus, e.g., due to therapeutic immunization. The relationships between time of ART initiation, duration of therapy, host immune responses, and kinetics of viral rebound are largely unknown. Given intriguing data indicating that certain host immune responses can contain nascent viral replication and even eliminate virus after low-dose SIV challenge, we propose a program of research on how host T cell responses might impact upon rebounding virus and/or the reservoir from which it springs. Prior studies have characterized rebound as a stochastic process that is most dependent on the number of reservoir cells remaining after ART cessation. We recognize the relevance of this factor but suggest that other reservoir characteristics are important. First, the activity of the viral reservoir, as assessed by cell-associated viral RNA, has recently been demonstrated to be a correlate of more rapid rebound. This finding is interesting because (i) it stimulates one to question if the latent and active reservoirs are separate pools, e.g., due to different viral integration sites, or a single pool of cells that stochastically re-activate transcription and because (ii) cells that are transcribing viral RNA might be vulnerable to host immune control. Second, the anatomic location of the viral reservoir might be important: it appears that RhCMV/SIV can contain viral replication to the portal of entry but have little impact following dissemination; thus, the same vaccines might contain spread of virus from a restricted reservoir. Finally, the phenotype of host cells harboring the reservoir would seem crucially important as their lifespan, anatomic location, vulnerability to antiretroviral drugs, interaction with innate or adaptive immunity, and indeed the kind of released virus will all differ. The objectives of our proposed program are: (i) to understand if host immunity impacts upon rebound via transformative effects on the reservoir itself, especially elimination of the active T cell reservoir; (ii) to understand if host immune responses can impact directly on viral replication or post-interruption setpoint in ways reminiscent of their demonstrated effects in primary SIV infection; and (iii) to test if HLA-E-restricted T cells have a qualitatively unique influence on viral rebound, as compared to effects of classical class Ia-restricted T cells or other host immune responses.

大多数停止服用抗逆转录病毒药物的HIV感染患者经历了快速病毒反弹，并且在 长期从较高的病毒载荷和较低的CD4+ T细胞计数中。即使在 长期以来被抑制了个人，例如几十年。因此，缓慢或不存在病毒 反弹只能在受限制的情况下发生，包括（i）早期开始抗逆转录病毒疗法， 导致储层细胞的主要感染，半衰期较短，（ii）在病毒储层下变化 艺术覆盖范围，例如，由于骨髓的准备BMT，或（iii）宿主的能力变化 由于治疗性免疫，对病毒的适应性免疫控制。时间之间的关系 艺术启动，治疗持续时间，宿主免疫反应和病毒反弹的动力学在很大程度上尚不清楚。 给定有趣的数据，表明某些宿主免疫反应可以包含新生的病毒复制和 即使在低剂量SIV挑战之后消除病毒，我们提出了一项有关宿主T细胞的研究计划 反应可能会影响反弹病毒和/或弹簧的水库。先前的研究已有 将反弹表征为一种随机过程，最取决于储层单元的数量 在停止艺术之后剩下。我们认识到这一因素的相关性，但建议其他储层 特征很重要。首先，通过细胞相关病毒RNA评估的病毒储层的活性， 最近已被证明是更迅速的反弹的相关性。这个发现很有趣，因为（i） 它刺激一个人质疑潜在的和主动的储层是否是独立的池，例如，由于病毒 积分位点，或一个随机重新激活转录的单个细胞池，因为（ii）细胞 转录病毒RNA可能容易受到宿主免疫控制的影响。第二，解剖位置的位置 病毒储层可能很重要：看来RHCMV/SIV可以在入口门户中包含病毒复制 但是传播后几乎没有影响；因此，相同的疫苗可能包含病毒的扩散 限制水库。最后，藏有储层的宿主细胞的表型似乎至关重要 作为其寿命，解剖位置，抗逆转录病毒药物的脆弱性，与先天或自适应的互动 免疫，实际上那种释放的病毒都会有所不同。 我们提出的计划的目标是：（i）了解宿主免疫是否对反弹产生影响 通过对储层本身的变革性影响，尤其是消除活性T细胞储存液； （ii） 了解宿主免疫反应是否会直接影响病毒复制或中断后影响 设定点让人想起它们在原发性SIV感染中所证明的影响； （iii）测试是否 与影响相比 经典IA限制的T细胞或其他宿主免疫反应的经典。