How IL-10R blockade can resolve persistent viral infections

描述(申请人提供)：最近，我相信我们做了一个非常了不起的观察，这可能会改变我们处理持续性病毒感染的方式。在暴露于淋巴细胞性脉络膜脑膜炎病毒(LCMV)变异株Clone 13后自然发生的迁延性感染的小鼠模型中，我们观察到产生了大量的IL-10，有趣的是，这与系统对病毒的细胞毒性T细胞反应的丧失不谋而合。在我们已发表的研究中，全身注射抗IL-10受体的抗体可迅速缓解持续感染，如治疗小鼠体重增加和病毒载量减少所证明的那样，没有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和创新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器T细胞来增强抗病毒反应。事实上，在以前的研究中，这种传统的方法未能解决LCMV Clone 13感染问题。因此，我们认为，阻断IL-10受体的治疗药物可能在治疗人类持续性病毒感染方面有很大的前景，如丙型肝炎病毒，可能还有艾滋病毒或巨细胞病毒。 在拟议的实验中，我们希望： 1.慢性感染如何诱导DC、CD4和CD8淋巴细胞产生IL-10。基于我们的发现，我们的工作假设是CD8a阴性的DC是抗病毒应答细胞产生IL-10的主要驱动因素。在慢性感染的小鼠中，这个亚群比CD8a阳性的DC相对丰富，因为CD8a是驱动抗病毒干扰素的DC？生产都被淘汰了。我们认为，这一亚群的早期病毒感染使它们在体内更容易受到CTL杀伤。 2.通过建立与PD-1/PD-1L阻断、抗病毒药物和抗病毒疫苗联合治疗的协同治疗范例，将IL-10R阻断的使用推广到临床 LCMV持续性感染与急性感染的直接比较将构成本次调查的基础。这一结果应该能够提供足够的洞察力，使这种新的治疗方法能够转化为人类持续性病毒感染。为了确保我们的发现能够到达那些从事艾滋病毒和丙型肝炎病毒研究的小组，已经与该领域的领导小组建立了合作关系。

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.