Targeting type I interferon-mediated activation restores immune function in chronic HIV infection
Targeting type I interferon-mediated activation restores immune function in chronic HIV infection
复制标题
DOI：
10.1172/jci89488
复制
发表时间：
2017-01-03
影响因子：
15.9
通讯作者：
Kitchen, Scott G.
中科院分区：
文献类型：
--
作者：
Zhen, Anjie;Rezek, Valerie;Kitchen, Scott G.
慢性免疫激活、免疫抑制和 T 细胞耗竭是 HIV 感染的标志，但驱动这些过程的机制尚不清楚。慢性激活可能是免疫衰竭的驱动力，I 型干扰素 (IFN-I) 正在成为 HIV 感染持续激活的关键成分。在这里，我们在慢性 HIV 感染的小鼠模型中测试了阻断 IFN-I 信号传导对 T 细胞反应和病毒复制的影响。使用感染 HIV 的人源化小鼠，我们证明在慢性 HIV 感染期间体内阻断 IFN-I 信号传导会减少 HIV 驱动的免疫激活，减少 T 细胞耗竭标志物表达，恢复 HIV 特异性 CD8 T 细胞功能，并导致病毒复制减少。与单独的 ART 治疗相比，抗逆转录病毒治疗 (ART) 与 IFN-I 阻断相结合可加速病毒抑制，进一步降低病毒载量，并减少持续感染的 HIV 病毒库。我们的数据表明，阻断 IFN-I 信号传导与 ART 治疗相结合可以恢复免疫功能，并可能减少慢性 HIV 感染期间的病毒储量，这为 IFN-I 阻断作为 HIV 感染的潜在疗法提供了验证。
Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection.