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

基本信息

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
项目类别：
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

项目摘要

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艾滋病毒感染者都会经历病毒快速反弹并遭受艾滋病毒的折磨。从长远来看，病毒载量较高，CD4+ T 细胞计数较低。即使在以下情况下，这种结果通常也会发生：个人受到长期压制，例如几十年。因此，缓慢或不存在的病毒反弹仅可能在有限的情况下发生，包括（i）早期开始抗逆转录病毒治疗，导致半衰期较短的储存细胞的主要感染，（ii）病毒储存库发生变化 ART 覆盖范围，例如，由于准备 BMT 时进行清髓术，或 (iii) 宿主的治疗能力发生变化对病毒的适应性免疫控制，例如由于治疗性免疫。时间之间的关系 ART 的启动、治疗的持续时间、宿主免疫反应和病毒反弹的动力学在很大程度上是未知的。鉴于有趣的数据表明某些宿主免疫反应可能包含新生病毒复制和甚至在低剂量 SIV 攻击后消除病毒，我们提出了一项关于宿主 T 细胞如何反应可能会影响反弹的病毒和/或病毒的储存库。先前的研究有将反弹描述为随机过程，最依赖于储存细胞的数量 ART 停止后剩余。我们认识到这个因素的相关性，但建议其他水库特征很重要。首先，通过细胞相关病毒 RNA 评估病毒库的活性，最近已被证明与更快的反弹有关。这一发现很有趣，因为 (i) 它促使人们质疑潜在的和活跃的储存库是否是不同的池，例如，由于不同的病毒整合位点，或随机重新激活转录的单个细胞池，并且因为（ii）细胞正在转录病毒 RNA 的病毒可能容易受到宿主免疫控制的影响。二、解剖位置病毒库可能很重要：RhCMV/SIV 似乎可以包含病毒复制到入口但传播后影响不大；因此，相同的疫苗可能会阻止来自不同来源的病毒传播限制水库。最后，携带储存库的宿主细胞的表型似乎至关重要因为它们的寿命、解剖位置、抗逆转录病毒药物的脆弱性、与先天或适应性的相互作用免疫力，甚至释放的病毒种类都会有所不同。我们提出的计划的目标是：（i）了解宿主免疫力是否会影响反弹通过对储存库本身的转化作用，特别是消除活性 T 细胞储存库； (二) 了解宿主免疫反应是否可以直接影响病毒复制或中断后设定点的方式让人想起它们在原发性 SIV 感染中所表现出的效果； (iii) 测试是否与效应相比，HLA-E 限制性 T 细胞对病毒反弹具有性质上独特的影响经典 Ia 类限制性 T 细胞或其他宿主免疫反应。