Defining HIV reservoirs that rebound following suspension of ART

摘要 在有效的艾滋病毒治疗方法问世以来的20年里，高风险人群中艾滋病毒感染成年人的寿命延长了。 资源设置已增加到未感染个体的十年内。然而，抗逆转录病毒药物 抗逆转录病毒治疗（ART）在恢复健康方面做得不够，如果停止治疗，病毒通常会反弹， 由于前病毒的持续存在和再活化，预处理水平降低。正在寻求治愈性疗法， 包括治疗性疫苗、与干细胞移植配对的化疗、嵌合抗原受体T 细胞，中和和免疫调节抗体，基因疗法，细胞因子和ART的启动， 急性感染虽然这些方法中的一些已经减少了传染性病毒的“储存库”，并且在一个实施例中， 如果一个病例可能治愈了艾滋病毒感染，那么更好地了解艾滋病毒持续存在的机制是 需要开发一种有效、安全和经济的治疗方法。艾滋病毒储存库主要建立在早期， 感染，虽然它们在ART期间衰减和成分变化，但维持水库的机制 只是部分已知。我们假设HIV的储存库是通过以下方式维持的：（1）整合的前病毒， 调节基因表达以促进这些细胞的存活，使受感染的细胞通过增殖而持续存在 （2）HIV特异性免疫应答由于T调节细胞的失调而耗尽 （3）表观遗传标记抑制前病毒DNA的表达， 感染的细胞由于前病毒的“深”潜伏期而持续存在。我们建议进行研究，以探讨这些作用， 使用从一个独特的比利时人身上前瞻性收集的标本， 在ART抑制期间以及ART治疗期间和之后， 分析治疗中断（ATI）。本研究的样本包括血液、脑脊液、骨髓， 支气管肺泡灌洗液、淋巴结、十二指肠、回肠和结肠。知识来自于 拟议的研究应指出可以测试并可能有助于 目标是开发一种治疗艾滋病毒感染的干预措施。

ABSTRACT In the twenty years since effective HIV treatments became available, the lifespan of HIV-infected adults in high- resource settings has increased to within a decade of uninfected individuals. Nevertheless, antiretroviral treatments (ART) fall short in restoring health, and if therapy is discontinued virus usually rebounds to pretreatment levels due the persistence and reactivation of proviruses. Curative therapies are being sought, including therapeutic vaccines, chemotherapies paired with stem-cell transplant, chimeric antigen receptor T cells, neutralizing and immune modulating antibodies, gene therapies, cytokines and initiation of ART during acute infection. While some of these approaches have reduced the “reservoirs” of infectious viruses and in one case may have cured HIV infection, a better understanding of the mechanisms underlying HIV persistence is needed to develop an effective, safe and economical cure. HIV reservoirs are primarily established early in infection, and while they decay and change in composition during ART, the mechanisms that sustain reservoirs are only partially known. We hypothesize that HIV reservoirs are maintained by: (1) Integrated proviruses that modulate gene expression to promote survival of these cells, allowing infected cells to persist by proliferation or latency; (2) HIV-specific immune responses become exhausted due to dysregulation of T-regulatory cells resulting from provirus integration; and (3) Epigenetic marks repress expression of proviral DNA, allowing infected cells to persist due to “deep” latency of proviruses. We propose studies to explore the role of these mechanisms in sustaining HIV reservoirs using specimens collected prospectively from a unique Belgian cohort of chronically infected individuals sampled during ART-suppression as well as during and after an analytical treatment interruption (ATI). Samples for this study include blood, cerebral spinal fluid, bone marrow, bronchioalveolar lavage fluid, lymph node, duodenum, ileum, and colon. The knowledge gained from the proposed studies should point to interventional strategies that could be tested and potentially contribute to the goal of developing an intervention to cure HIV infection.