How IL-10R blockade can resolve persistent viral infections

描述（由申请人提供）：最近，我相信，我们做了一个非常了不起的观察，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丛脑膜炎病毒（LCMV）变体克隆13后自然发生的小鼠慢性感染模型中，我们观察到大量IL-10的产生，有趣的是，这与针对病毒的全身细胞毒性T细胞反应的丧失相吻合。在我们发表的研究中，在没有全身副作用或免疫病理的情况下，全身给药一种针对IL-10受体的抗体导致持续感染的快速解决，正如治疗小鼠体重增加和病毒载量降低所证明的那样。这种治疗持续性病毒感染的成功和创新方法与传统的疫苗策略不同，传统的疫苗策略试图通过直接诱导或扩增抗病毒效应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克隆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（如HCV和可能的HIV或CMV）有很大的希望。

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.