Immune based interventions for HIV eradication

 描述（由申请人提供）：尽管艾滋病研究取得了许多重大进展，包括开发和优化了有效的抗逆转录病毒疗法（ART），成功地抑制了大多数HIV感染者的病毒复制，但仍然没有治愈这种致命感染的治疗方法。ART治疗的HIV感染者的残留疾病主要包括（i）持续性免疫异常（包括炎症、有限的CD 4 T细胞重建和过早的免疫衰老），这可能最终导致所谓的“HIV相关的终末器官疾病”，以及（ii）存在潜伏感染细胞的持久储库，这些细胞不受ART影响，并导致病毒复制的快速反弹如果ART停止。在缺乏能够治愈艾滋病毒感染的可扩展治疗方法的情况下，ART是一种终身治疗方法，在成本和临床安全性方面带来了重大挑战。由于这些原因，根除或至少在功能上治愈艾滋病毒感染将对全球健康产生重大影响。残余炎症可能通过几种机制促进ART下的HIV持续存在，包括驱动维持储库持续存在的易感细胞的感染，以及HIV特异性抗病毒免疫应答的耗尽。因此，一个恶性循环可能会被触发，其中残留的炎症，无效的抗病毒免疫反应和HIV持续存在密切相关。因此，有一个强烈的共识，即艾滋病毒感染的治愈不会通过单独的ART强化实现，并且可能需要旨在限制残留炎症和改善抗病毒免疫应答的新方法。该项目的总体目标是探索一种新型的联合白细胞介素（IL）-21和IFN α（IFNa）干预在ART治疗的SIV感染恒河猴（RM）中的治疗潜力。我们认为，IL-21和IFNa的顺序给药是安全的，并将通过减少免疫功能障碍和炎症（通过IL-21）以及增强由许多宿主限制因子介导的抗病毒功能（通过IFNa）对HIV持续性产生强烈的协同作用。这些假设将在目标1和2中得到检验。此外，我们提出了一系列机制研究，旨在确定IL-21和IFNa顺序给药的分子和细胞效应[目的3]。如果我们的假设是正确的，拟议的研究将提供在最相关的HIV感染临床前动物模型中连续使用IL-21和IFNa治疗后炎症减少，免疫功能改善和病毒库减少的体内证据，并使用两种分子作为单一药剂，正在测试（IL-21）或FDA批准（IFNa）用于治疗多种人类疾病。如果成功，拟议的基于免疫的干预措施将在人体临床试验中进行测试，以评估其作为HIV感染功能性治疗的潜力。

 DESCRIPTION (provided by applicant): Despite many major advances in AIDS research, including the development and optimization of potent anti- retroviral therapy (ART) that successfully suppresses virus replication in the majority of HIV-infected individuals, a treatment that can cure this deadly infection is still not available. Residual disease in ART-treated HIV-infected individuals consists mainly of (i) persistent immune abnormalities (including inflammation, limited CD4 T cell reconstitution, and premature immune senescence) which may ultimately lead to the so-called "HIV- associated end-organ diseases", and (ii) the presence of persistent reservoirs of latently infected cells that are not affected by ART and are responsible for the rapid rebound of virus replication if ART is stopped. In the absence of a scalable treatment able to cure HIV infection, ART is a lifelong treatment that poses significant challenges in terms of costs and clinical safety. For these reasons, eradicating or at least functionally curing HIV infection would have a remarkable impact on global health. Residual inflammation may promote HIV persistence under ART by several mechanisms, including driving the infection of susceptible cells that sustain the persistence of the reservoir, and the exhaustion of HIV-specific antiviral immune responses. Thus, a vicious cycle may be triggered in which residual inflammation, ineffective antiviral immune responses, and HIV persistence are intimately connected. As such, there is a strong consensus that a cure for HIV infection will not be achieved through ART intensification alone, and that novel approaches aimed at limiting residual inflammation and improving antiviral immune responses may be needed. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and Interferon-a (IFNa) intervention in ART-treated SIV-infected rhesus macaques (RMs). We propose that the sequential administration of IL-21 and IFNa is safe and will have a strong synergistic effect on HIV persistence by decreasing immune dysfunction and inflammation (via IL-21), as well as enhancing antiviral functions mediated by a number of host restriction factors (via IFNa). These hypotheses will be tested in Aims 1 and 2. Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of sequential administration of IL-21 and IFNa [Aim 3]. If our hypothesis is correct, the proposed studies will provide in vivo evidence of reduced inflammation, improved immune function, and decreased virus reservoirs following sequential IL-21 and IFNa treatment in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested (IL-21) or approved by the FDA (IFNa) for treatment of several human diseases. If successful, the proposed immune based intervention would then be tested in human clinical trials to assess its potential as a functional cure for HIV infection.