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

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的快速反弹，并在 较高的病毒载量和较低的CD4+T细胞计数会导致更长的时间。这种结果通常会发生，即使在 个人被压制了很长一段时间，例如几十年。因此，缓慢或根本不存在的病毒 反弹只有在有限的情况下才会发生，包括(1)及早开始抗逆转录病毒治疗， 导致以较短的半衰期为主的水库细胞的感染，(Ii)病毒水库在 抗逆转录病毒治疗的覆盖率，例如，由于为骨髓移植做准备而进行的骨髓清除术，或(Iii)宿主对 对病毒的适应性免疫控制，例如，由于治疗性免疫。时间和时间之间的关系 ART的启动、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是未知的。 鉴于耐人寻味的数据表明某些宿主免疫反应可以包含新生病毒复制和 即使在低剂量SIV攻击后也能清除病毒，我们提出了一个研究宿主T细胞如何 应对措施可能会对反弹的病毒和/或病毒的来源产生影响。先前的研究已经 将反弹描述为最依赖于储集层细胞数量的随机过程 在艺术停止后留下来。我们认识到这一因素的相关性，但建议其他储藏者 特色很重要。首先，通过细胞相关病毒RNA来评估病毒库的活性， 最近被证明与更快速的反弹相关。这一发现很有趣，因为(I) 这激发了人们对潜在和活跃的水库是否是独立的池的质疑，例如，由于不同的病毒 整合部位，或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。第二，尺骨的解剖位置 病毒库可能很重要：似乎RhCMV/SIV可以包含病毒复制到进入门户 但在传播后影响不大；因此，相同的疫苗可能会遏制病毒从 受限储集层。最后，寄主细胞的表型似乎至关重要。 因为他们的寿命、解剖位置、对抗逆转录病毒药物的易感性、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。 我们建议的计划的目标是：(I)了解宿主免疫是否影响反弹 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；(Ii) 了解宿主免疫反应是否会直接影响病毒复制或中断后 设定点的方式使人想起它们在初次SIV感染中所展示的效果；以及(Iii)测试是否 与效应相比，人类白细胞抗原-E限制性T细胞对病毒反弹有独特的影响 经典的Ia类限制性T细胞或其他宿主免疫反应。

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.