Boosting anti-HIV immunity through manipulation of Tfh function.

描述(由申请人提供)：在大多数艾滋病毒感染者中，病毒抑制只能通过抗逆转录病毒疗法实现。尽管抗逆转录病毒治疗后炎症和免疫激活显著减少，但接受抗逆转录病毒治疗的患者仍表现出这两种活动的低水平，导致严重的免疫功能障碍，表现为无法产生和维持T细胞和B细胞免疫。此外，ART治疗会导致长期和短期的毒性，导致心血管疾病和其他并发症。我们最近报道了在接受抗逆转录病毒治疗的病毒抑制患者中，记忆中的CD4区出现了显著的功能障碍。我们还发现了记忆B细胞室的类似缺陷，与自然控制者相比，这些细胞过早死亡，产生的抗HIV抗体水平明显较低。即使在感染后的头几周接受治疗，在停止抗逆转录病毒治疗后，也只有一小部分艾滋病毒感染者能够遏制病毒血症。然而，绝大多数艾滋病毒感染者表现出病毒血症的死灰复燃，表明在没有抗逆转录病毒治疗的情况下，免疫系统无法遏制病毒复制。这为开发新的免疫疗法提供了强有力的理由，这些疗法旨在在没有抗逆转录病毒治疗的情况下增强慢性感染者的抗艾滋病毒免疫，目的是实现功能性治愈。因此，在病毒抑制的受试者中，在治疗中断时无法实现对艾滋病毒的功能性免疫反应是一个主要问题。因此，对于大多数艾滋病毒感染者(超过85%)来说，在没有抗逆转录病毒治疗的情况下获得抗艾滋病毒免疫的目标只有在增强适应性免疫反应的情况下才可能实现。在这项提议中，我们将研究可能导致他们免疫反应缺陷的潜在机制，以努力朝着实现功能性治愈的方向迈进一步。我们将在一个有根据的假设下进一步工作，即增强CD4+Tfh/B细胞轴对于获得更好的抗HIV免疫至关重要。

DESCRIPTION (provided by applicant): Viral suppression in the majority of HIV infected subjects can only be achieved with ART. Despite the significant decrease in inflammation and immune activation following ART, people under ART still exhibit low levels of both these activities leading to significant immune dysfunction that is illustrated by the inability to generae and maintain T cell and B cell immunity. Furthermore, ART therapy induces long and short-term toxicities leading to cardiovascular diseases and other complications. We have recently reported a significant dysfunction in the memory CD4 compartment in virally suppressed individuals undergoing ART. We have also shown a similar defect in the memory B cell compartment with these cells dying prematurely and producing significantly lower levels of anti-HIV antibodies when compared to natural controllers. Even when treated in the first few weeks after infection, only a small percentage of HIV infected subjects are able to contain viremia upon cessation of ART. Whereas, the large majority of HIV infected individuals exhibit resurgence of viremia demonstrating the inability of the immune system to contain viral replication in the absence of ART. This provides a strong rationale to develop novel immunotherapies that aim at augmenting anti-HIV immunity in chronically infected individuals in the absence of ART with the purpose of achieving a functional cure. Thus the inability to achieve a functional immune response against HIV upon treatment interruption in virally suppressed subjects is a major problem. Thus, for the majority of HIV infected individuals (more than 85%), the goal of acquiring anti-HIV immunity in the absence of ART is only possible with the augmentation of adaptive immune responses. In this proposal we will study the underlying mechanisms that could be responsible for their defective immune response in an effort of moving closer towards achieving a functional cure. We will further work under the educated assumption that enhancing the CD4+Tfh/B cell axis is critical for attaining improved anti-HIV immunity.