Project 1. Defining Virologic and Immunologic Factors Predicting the Probability of Post-Treatment HIV Control

摘要 抗逆转录病毒疗法阻断HIV复制，但不能治愈，因为静止整合的HIV DNA不能 被传统药物根除潜伏感染细胞的HIV储库在感染患者中无限期存在 即使经过长期治疗，如果停止治疗，也会导致病毒迅速反弹。我们 鉴定了一些在治疗中止后能够持久控制病毒血症的患者（治疗后）， 治疗控制人员）介绍了艾滋病毒持续缓解的概念，并提供了 这种状态至少在某些患者中是可以实现的。PTC中的HIV缓解的特征是 感染细胞的存在，虽然在低水平。这意味着这种长期病毒控制的情况 需要HIV-1和宿主之间平衡的相互作用。然而，有趣的是，PTC没有遗传， 临床或免疫学特征，常见于罕见的患者能够自然控制 HIV-1无治疗干预（HIV控制者）。HIV缓解似乎受到早期 开始抗逆转录病毒治疗并在停止前维持数年。我们认为 PTC受益于早期治疗，限制了病毒库的建立，并允许 最佳的成熟/引发和关键免疫应答的保存。然而，只有一小部分 早期和持久治疗的患者能够在治疗中断后控制感染。因此， 迫切需要确定与治疗后感染控制相关的确切机制， 预测cART停药结果的生物标志物。为此，有必要更好地了解 (i)建立和维持细胞HIV库的动力学，（ii） 免疫应答和感染细胞，以及（iii）早期cART对这些参数的影响。 我们将比较PTCs和长期有效的PTCs患者的免疫学和病毒学参数。 cART，在原发性或慢性HIV感染期间启动。我们将使用实证分析和数学 建模，以（i）定义保护的相关性，可以识别接受ART的患者， 实现艾滋病毒缓解的可能性;以及（ii）提供治疗效果的详细描述 启动的模式和大小的病毒水库和免疫反应，以及如何影响 治疗开始时病毒反弹的动力学。为了开发这个项目，我们将受益于获得 ANRS PRIMO和ANRS VISCONTI队列患者的独特样本和经验数据 在66只SIV感染的猕猴在不同时间开始cART的大型非人灵长类动物研究中产生 并在中断前维持治疗2年。

ABSTRACT Antiretroviral therapy blocks HIV replication, but is not curative, as quiescent integrated HIV DNA is not eradicated by classical drugs. HIV reservoirs of latently infected cells persist indefinitely in infected patients even after long-term periods of treatment and cause rapid viral rebound if the treatment is stopped. Our identification of some patients who were able to durably control viremia after therapy discontinuation (Post- Treatment Controllers, PTCs) introduced the concept of sustained HIV remission and provided proof of concept that such status is achievable at least in some patients. HIV remission in PTCs is characterized by the presence of infected cells, although at low levels. This implies that this situation of long-term viral control requires balanced interactions between HIV-1 and the host. Yet, intriguingly, PTCs do not have the genetic, clinical or immunological characteristics that are commonly found in the rare patients able to naturally control HIV-1 without therapeutic intervention (HIV controllers). HIV remission appears to be favored by the early initiation of antiretroviral treatment and its maintenance for several years before discontinuation. We believe that PTCs benefited from an early treatment that limited the establishment of viral reservoirs and allowed optimal maturation/priming and preservation of critical immune responses. However, only a small fraction of early and durably treated patients are able to control infection after treatment interruption. There is therefore an urgent need to identify the precise mechanisms associated with post-treatment control of infection and define biomarkers that predict the outcome of cART discontinuation. For this, it will be essential to better understand (i) the dynamics of the establishment and maintenance of cellular HIV reservoirs, (ii) the interplay between immune responses and infected cells, and (iii) the impact of early cART on these parameters. We will compare immunological and virological parameters in PTCs and in patients on effective long-term cART, initiated during primary or chronic HIV-infection. We will use empirical analyses and mathematical modeling to (i) define correlates of protection that could identify ART-receiving patients with the highest probability to achieve HIV remission; and (ii) provide a detailed characterization of the effect of treatment initiation on the pattern and the size of the viral reservoirs and immune responses and how this impact the dynamics of viral rebound at the time of treatment initiation. To develop this project we will benefit of access to unique samples from patients in ANRS PRIMO and ANRS VISCONTI Cohorts and to the empirical data generated in a large non-human primate study of 66 SIV-infected macaques initiating cART at different times and maintaining the treatment for 2 years before interruption.