Mu Wenli, Martin Heather, Zhen Anjie
Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Autophagy Rep. 2023;2(1). doi: 10.1080/27694127.2023.2254615. Epub 2023 Sep 11.
Chronic immune activation and inflammation are hallmarks of Human Immunodeficiency Virus-1 (HIV-1) pathogenesis. Therefore, approaches to safely reduce systematic inflammation are essential to improve immune responses and thus slow or prevent HIV progression. Autophagy is a cellular mechanism for the disposal of damaged organelles and elimination of intracellular pathogens. It is not only vital for energy homeostasis, but also plays a critical role in regulating immunity. However, how it regulates inflammation and antiviral T cell responses during HIV infection is unclear. Our study demonstrated that impairment of autophagy leads to spontaneous type I-Interferons (IFN-I) signaling, while autophagy induction reduces IFN-I signaling in macrophages. Importantly, we demonstrated that in vivo treatment of autophagy inducer rapamycin in chronically HIV infected humanized mice decreased chronic IFN-I signaling, improved exhausted anti-viral T cell function, and reduced viral loads. Taken together, our study supports the therapeutic potential of rapamycin and potentially other autophagy inducers in alleviating HIV-1 immunopathogenesis and improving anti-viral T cell responses.
慢性免疫激活和炎症是人类免疫缺陷病毒1型（HIV-1）发病机制的标志。因此，安全减轻系统性炎症的方法对于改善免疫反应从而减缓或预防HIV进展至关重要。自噬是一种处理受损细胞器和清除细胞内病原体的细胞机制。它不仅对能量稳态至关重要，而且在调节免疫中也起着关键作用。然而，在HIV感染期间它如何调节炎症和抗病毒T细胞反应尚不清楚。我们的研究表明，自噬受损会导致自发性I型干扰素（IFN-I）信号传导，而自噬诱导会降低巨噬细胞中的IFN-I信号传导。重要的是，我们证明在慢性HIV感染的人源化小鼠中体内给予自噬诱导剂雷帕霉素可降低慢性IFN-I信号传导，改善耗竭的抗病毒T细胞功能，并降低病毒载量。综上所述，我们的研究支持雷帕霉素以及潜在的其他自噬诱导剂在减轻HIV-1免疫发病机制和改善抗病毒T细胞反应方面的治疗潜力。
