Antiretroviral therapy (ART) transformed HIV from a life-threatening disease to a chronic condition. However, eliminating the virus remains an elusive therapy goal. For several decades, Friend virus (FV) infection serves as a murine model to study retrovirus immunity. Similar to HIV, FV persists at low levels in lymph nodes B cell follicles avoiding elimination by immune cells. Such immune-privileged reservoirs exclude cytotoxic T cells from entry. However, CXCR5+ T cells are permitted to traffic through germinal centers. This marker is predominantly expressed by CD4+ follicular helper T cells (Tfh). Therefore, we explored immunotherapy to induce cytotoxic Tfh, which are rarely found under physiological conditions. The TNF receptor family member CD137 was first identified as a promising target for cancer immunotherapy. We demonstrated that FV-infected mice treatment with αCD137 antibody resulted in an induction of the cytotoxic program in Tfh. The therapy significantly increased numbers of cytotoxic Tfh within B cell follicles and contributed to viral load reduction. Moreover, αCD137 antibody combined with ART delayed virus rebound upon treatment termination without disturbing the lymph node architecture or antibody responses. Thus, αCD137 antibody therapy might be a novel strategy to target the retroviral reservoir and an interesting approach for HIV cure research.

中文翻译：

---

免疫疗法诱导的细胞毒性 T 滤泡辅助细胞减少了 B 细胞滤泡中受逆转录病毒感染的储存细胞的数量。

抗逆转录病毒疗法（ART）将艾滋病毒从一种危及生命的疾病转变为一种慢性疾病。然而，消除病毒仍然是一个难以捉摸的治疗目标。几十年来，弗兰德病毒（FV）感染一直作为研究逆转录病毒免疫的小鼠模型。与 HIV 类似，FV 在淋巴结 B 细胞滤泡中持续保持低水平，避免被免疫细胞消除。这种免疫豁免储存库将细胞毒性 T 细胞排除在外。然而，CXCR5+ T 细胞被允许通过生发中心。该标记物主要由 CD4+ 滤泡辅助 T 细胞 (Tfh) 表达。因此，我们探索了免疫疗法来诱导细胞毒性 Tfh，这在生理条件下很少发现。TNF 受体家族成员 CD137 首次被确定为癌症免疫治疗的有希望的靶点。我们证明，用 αCD137 抗体治疗 FV 感染的小鼠可诱导 Tfh 中的细胞毒性程序。该疗法显着增加了 B 细胞滤泡内细胞毒性 Tfh 的数量，并有助于减少病毒载量。此外，αCD137抗体与ART相结合可延迟治疗终止时的病毒反弹，而不会干扰淋巴结结构或抗体反应。因此，αCD137抗体疗法可能是一种针对逆转录病毒库的新策略，也是艾滋病毒治疗研究的一种有趣方法。