Mu Wenli, Kedia Nandita, Zhen Anjie
Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Viruses. 2025 May 29;17(6):774. doi: 10.3390/v17060774.
Type I interferons (IFN-Is) play a dual role in the immune response to HIV-1, providing early antiviral defense while driving immune dysfunction in the chronic phase. During acute infection, robust IFN signaling is critical in controlling viral replication, activating innate immunity, and limiting reservoir establishment. However, sustained IFN-I activation during chronic infection fuels systemic inflammation, immune exhaustion, and fibrosis, particularly in lymphoid tissues such as gut-associated lymphoid tissue (GALT). Prolonged IFN-I exposure upregulates inhibitory receptors on T cells, impairs metabolic fitness, and fosters an immunosuppressive cytokine milieu that weakens overall immune responses. In contrast to natural SIV (Simian immunodeficiency virus) hosts, IFN-I responses are tightly regulated to prevent chronic immune activation and tissue damage. However, humans and non-natural hosts experience persistent Interferon Stimulated Gene (ISG) expression and IFN-I driven inflammation. Emerging therapeutic strategies seek to harness the antiviral benefits of IFN-I while mitigating its pathogenic effects. Approaches such as the IFNAR blockade, autophagy induction, JAK-STAT inhibition, and combined immune inhibitory blockade therapy show promise in restoring immune balance and enhancing T cell function. This review examines the mechanisms of IFN-I dysregulation in chronic HIV-1 infection and highlights novel interventions aimed at finetuning IFN-I signaling for therapeutic benefit.
I型干扰素（IFN-I）在对HIV-1的免疫反应中发挥双重作用，在提供早期抗病毒防御的同时，在慢性期引发免疫功能障碍。在急性感染期间，强大的IFN信号传导对于控制病毒复制、激活先天免疫和限制病毒库的建立至关重要。然而，慢性感染期间持续的IFN-I激活会加剧全身炎症、免疫耗竭和纤维化，尤其是在肠道相关淋巴组织（GALT）等淋巴组织中。长时间暴露于IFN-I会上调T细胞上的抑制性受体，损害代谢适应性，并促进免疫抑制性细胞因子环境，从而削弱整体免疫反应。与天然猴免疫缺陷病毒（SIV）宿主不同，IFN-I反应受到严格调节以防止慢性免疫激活和组织损伤。然而，人类和非天然宿主会经历持续的干扰素刺激基因（ISG）表达和IFN-I驱动的炎症。新出现的治疗策略旨在利用IFN-I的抗病毒益处，同时减轻其致病作用。诸如IFNAR阻断、自噬诱导、JAK-STAT抑制和联合免疫抑制阻断疗法等方法在恢复免疫平衡和增强T细胞功能方面显示出前景。本综述探讨了慢性HIV-1感染中IFN-I失调的机制，并强调了旨在微调IFN-I信号传导以获得治疗益处的新干预措施。
