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: 9332144
• 负责人: Peter A Barry
• 金额: $ 148.42万
• 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/9332144
• 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; Immunization; 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; Therapeutic; 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; 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.

大多数艾滋病毒感染者停止服用抗逆转录病毒药物后，病毒迅速反弹， 从更高的病毒载量和更低的CD 4 + T细胞计数。这种结果通常发生在 个体已经被抑制了很长时间，例如，几十年因此，缓慢或不存在的病毒 只有在有限的情况下才可能发生反弹，包括（i）早期开始抗逆转录病毒治疗， 导致具有较短半衰期的储库细胞的主要感染，（ii）在感染后病毒储库的变化， 抗逆转录病毒治疗覆盖率，例如，由于骨髓消融准备BMT，或（iii）在主机的能力的变化， 对病毒的适应性免疫控制，例如，由于治疗性免疫。时间的关系 ART的启动、治疗持续时间、宿主免疫应答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以包含新生病毒复制， 甚至在低剂量SIV攻击后消除病毒，我们提出了一个研究宿主T细胞如何 反应可能影响反弹的病毒和/或其来源的宿主。先前的研究 特征反弹作为一个随机过程，这是最依赖于水库细胞的数量 停止抗逆转录病毒治疗后的剩余时间。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评估病毒库的活性， 最近被证明是更快速反弹的相关因素。这个发现很有趣，因为（i） 它促使人们质疑潜在的和活动的储层是否是分开的储层，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库，并且因为（ii） 可能容易受到宿主免疫控制。第二，解剖位置 病毒库可能是重要的：RhCMV/SIV似乎可以将病毒复制包含到入口 但在传播后几乎没有影响;因此，同样的疫苗可能会遏制病毒从一个 限制性水库最后，宿主细胞的表型似乎至关重要 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，以及释放的病毒种类都是不同的。 我们提出的计划的目标是：（i）了解宿主免疫力是否影响反弹 通过对储库本身的转化作用，特别是消除活性T细胞储库;（ii） 了解宿主免疫反应是否会直接影响病毒复制或中断后 设定点的方式让人想起他们在原发性SIV感染的表现效果;和（iii）测试，如果 HLA-E限制性T细胞对病毒反弹具有定性独特的影响， 经典的Ia类限制性T细胞或其他宿主免疫反应。