How IL-10R blockade can resolve persistent viral infections

描述（由申请人提供）：我相信，最近我们做了一个非常了不起的观察，它可能会改变我们处理持续性病毒感染的方式。在接触淋巴细胞性脉络膜脑膜炎病毒 (LCMV) 变体克隆 13 后自然发生的长期感染的小鼠模型中，我们观察到产生了大量的 IL-10，有趣的是，这与针对该病毒的全身细胞毒性 T 细胞反应的丧失相一致。在我们发表的研究中，系统性施用针对 IL-10 受体的抗体可快速解决持续性感染，如治疗小鼠体重增加和病毒载量减少所证明，且不存在全身副作用或免疫病理学。这种治疗持续性病毒感染的成功且创新的方法与传统疫苗策略不同，传统疫苗策略试图通过直接诱导或放大抗病毒效应T细胞来增强抗病毒反应。事实上，在之前的研究中，这种传统方法未能解决 LCMV Clone 13 感染。因此，我们认为阻断 IL-10 受体的治疗药物可能对治疗人类持续性病毒感染（例如 HCV 以及可能的 HIV 或 CMV）具有广阔的前景。 在提议的实验中，我们希望： 1. 慢性感染如何引起 DC、CD4 和 CD8 淋巴细胞全身产生 IL-10。根据我们的发现，我们的工作假设是 CD8a 阴性 DC 是抗病毒应答细胞产生 IL-10 的主要驱动力。在慢性感染小鼠中，该子集比 CD8a 阳性 DC 相对丰富，因为 CD8 a pos DC 驱动抗病毒 IFN？生产，被淘汰。我们认为，该亚群的早期病毒感染使它们更容易在体内被 CTL 杀死。 2. 通过建立与PD-1/PD-1L阻断剂、抗病毒药物和抗病毒疫苗联合治疗的协同范例，将IL-10R阻断剂的应用转化为临床 LCMV 持续感染与急性感染的直接比较将构成本次调查的基础。研究结果应提供足够的见解，使这种新疗法能够应用于人类持续性病毒感染。为了确保我们的研究结果能够传达给那些从事艾滋病毒和丙型肝炎工作的团体，我们与该领域的领先团体建立了合作。

DESCRIPTION (provided by applicant): Recently, we made, I believe, a quite remarkable observation that could change how we deal with persistent viral infections. In a murine model of protracted infection that naturally occurs after exposure to the lymphocytic choriomeningitis virus (LCMV) variant Clone 13, we observed that a significant amount of IL-10 is produced, which interestingly coincides with the loss of the systemic cytotoxic T cell response against the virus. In our published studies, systemic administration of an antibody against the IL-10 receptor led to rapid resolution of the persistent infection, as demonstrated by weight gain and reduced viral load in the treated mice, in the absence of systemic side effects or immunopathology. This successful and innovative approach to treating a persistent viral infection constitutes a departure from classical vaccine strategies that have attempted to enhance the anti-viral response by directly inducing or amplifying anti-viral effector T cells. Indeed, such conventional approaches have failed to resolve LCMV Clone 13 infection in previous studies. We therefore suggest that therapeutic agents that block IL-10 receptor may hold great promise for the treatment of persistent viral infections in humans such as HCV and possibly HIV or CMV. In the proposed experiments, we would like to: 1. How chronic infection elicits systemic IL-10 production from DCs, CD4 and CD8 lymphocytes. Based on our findings, our working hypothesis is that CD8a negative DCs are the main drivers of IL-10 production from anti-viral responder cells. This subset is relatively enriched over CD8a positive DCs in chronically infected mice, because CD8 a pos DCs, which drive anti-viral IFN? production, are eliminated. We propose that early viral infection of this subset renders them more susceptible to CTL killing in vivo. 2. Translate the use of IL-10R blockade to the clinic by establishing paradigms for synergy in combination therapies with PD-1/PD-1L blockade, antiviral drugs and anti-viral vaccines A direct comparison of persistent versus acute infection with LCMV will form the basis for this investigation. The results should offer sufficient insight to enable the translation of this novel treatment to human persistent viral infections. In order to assure that our findings reach those groups working on HIV and HCV, cooperations have been established with leading groups in the field.