CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV RNA that are not cleared efficiently by adaptive immune responses. Analysis of viral tropism revealed that CHIKV RNA was present preferentially in splenic B cells and follicular dendritic cells during the persistent phase of infection, and animals lacking B cells did not develop persistent CHIKV infection in lymphoid tissue. Anti-CD137 MAb treatment resulted in T cell-dependent clearance of CHIKV RNA in lymphoid tissue, although this effect was not observed in musculoskeletal tissue. The clearance of CHIKV RNA from lymphoid tissue by anti-CD137 MAb was associated with reductions in the numbers of germinal center B cells and follicular dendritic cells. Similar results were observed with anti-CD137 MAb treatment of mice infected with Mayaro virus, a related arthritogenic alphavirus. Thus, anti-CD137 MAb treatment promotes resolution of chronic alphavirus infection in lymphoid tissues by reducing the numbers of target cells for infection and persistence.IMPORTANCE Although CHIKV causes persistent infection in lymphoid and musculoskeletal tissues in multiple animals, the basis for this is poorly understood, which has hampered pharmacological efforts to promote viral clearance. Here, we evaluated the therapeutic effects on persistent CHIKV infection of an agonistic anti-CD137 MAb that can activate T cell and natural killer cell responses to clear tumors. We show that treatment with anti-CD137 MAb promotes the clearance of persistent alphavirus RNA from lymphoid but not musculoskeletal tissues. This occurs because anti-CD137 MAb-triggered T cells reduce the numbers of target germinal center B cells and follicular dendritic cells, which are the primary reservoirs for CHIKV in the spleen and lymph nodes. Our studies help to elucidate the basis for CHIKV persistence and begin to provide strategies that can clear long-term cellular reservoirs of infection.

中文翻译：

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基孔肯雅病毒感染在淋巴组织中的清除通过用抗CD137激动剂治疗而得到促进。

CD137是细胞表面蛋白的肿瘤坏死因子受体超家族的成员，在T细胞，自然杀伤细胞，B细胞亚群和某些树突状细胞上充当共刺激受体。在人类癌症试验中，激动性抗CD137单克隆抗体（MAb）治疗已与其他化学治疗剂联合使用。基于其促进肿瘤清除的能力，我们假设抗CD137 MAb可能会激活免疫反应并解决慢性病毒感染。我们在基孔肯雅病毒（CHIKV）的小鼠感染模型中评估了抗CD137 MAb疗法，这是一种在人类中引起慢性多关节炎的甲型病毒，与CHIKV RNA的储库相关，而该库未通过适应性免疫反应有效清除。病毒嗜性分析表明，在感染的持续阶段，脾脏B细胞和滤泡树突状细胞中优先存在CHIKV RNA，而缺乏B细胞的动物在淋巴组织中并未发生持续的CHIKV感染。抗CD137 MAb治疗可导致淋巴组织中CHIKV RNA的T细胞依赖性清除，尽管在肌肉骨骼组织中未观察到这种作用。抗CD137 MAb从淋巴样组织清除CHIKV RNA与生发中心B细胞和滤泡树突状细胞数量减少有关。用抗CD137 MAb处理被Mayaro病毒（一种相关的致关节炎的alpha病毒）感染的小鼠，观察到了相似的结果。从而，抗CD137 MAb治疗通过减少感染和持久性靶细胞的数量来促进淋巴组织中慢性α病毒感染的消退。已经阻碍了促进病毒清除的药理工作。在这里，我们评估了一种激动性抗CD137 MAb对持续性CHIKV感染的治疗效果，该抗CD137 MAb可以激活T细胞和自然杀伤细胞应答以清除肿瘤。我们显示抗CD137单抗的治疗可促进从淋巴组织而非肌肉骨骼组织清除持久性α病毒RNA。发生这种情况是因为抗CD137 MAb触发的T细胞减少了目标生发中心B细胞和滤泡树突状细胞的数量，它们是CHIKV在脾和淋巴结中的主要储存库。我们的研究有助于阐明CHIKV持久性的基础，并开始提供可以清除长期感染细胞库的策略。