Autophagy inducer rapamycin treatment reduces IFN-I–mediated Inflammation and improves anti–HIV-1 T cell response in vivo
Wenli Mu, … , Scott G. Kitchen, Anjie Zhen
Wenli Mu, … , Scott G. Kitchen, Anjie Zhen
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e159136. https://doi.org/10.1172/jci.insight.159136.
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Research Article AIDS/HIV Inflammation

Autophagy inducer rapamycin treatment reduces IFN-I–mediated Inflammation and improves anti–HIV-1 T cell response in vivo

Abstract

A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses. Autophagy is a cellular mechanism for disposal of damaged organelles and elimination of intracellular pathogens. Autophagy is pivotal for energy homeostasis and plays critical roles in regulating immunity. However, how it regulates inflammation and antiviral T cell responses during HIV infection is unclear. Here, we demonstrate that autophagy is directly linked to IFN-I signaling, which is a key driver of immune activation and T cell exhaustion during chronic HIV infection. Impairment of autophagy leads to spontaneous IFN-I signaling, and autophagy induction reduces IFN-I signaling in monocytic cells. Importantly, in HIV-1–infected humanized mice, autophagy inducer rapamycin treatment significantly reduced persistent IFN-I–mediated inflammation and improved antiviral T cell responses. Cotreatment of rapamycin with ART led to significantly reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy is a promising approach to treat persistent inflammation and improve immune control of HIV replication.

Authors

Wenli Mu, Valerie Rezek, Heather Martin, Mayra A. Carrillo, Shallu Tomer, Philip Hamid, Miguel A. Lizarraga, Tristan D. Tibbe, Otto O. Yang, Beth D. Jamieson, Scott G. Kitchen, Anjie Zhen

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Figure 2

Autophagy induction by rapamycin (Rapa) reduces IFN-I signaling in activated macrophages and THP1 cells and is dependent on ATG5.

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Autophagy induction by rapamycin (Rapa) reduces IFN-I signaling in activ...
CD14+ monocytes were sorted from healthy primary PBMCs with CD14 microbeads and differentiated into macrophages with macrophage colony-stimulating factor at 10 ng/mL for 3 days. Afterward, cells were treated with the autophagy inducers rapamycin (50 pM and 500 pM) or spermidine (Spe; 10 nM and 100 nM) for 2 days. (A) Autophagy flux was measured by western blotting for LC3 and actin. The ratio of LC3-II/actin was calculated by ImageJ. After rapamycin or spermidine treatment, cells were stimulated by (B) LPS or (C) cGAMP for 6 hours; the ISG MX1 and internal control HPRT1 were measured by real-time PCR. (D and E) THP-1 scram (D) or THP-1 ATG5-sg52 (E) cells were treated with 50 pM rapamycin or 100 nM spermidine for 2 days and followed by cGAMP stimulation for 6 hours. The ISGs MX1 and IRF7 and the internal control HPRT1 were measured by real-time PCR. Data are reported as the mean values of 3–5 independent experiments ± SEM. *P < 0.05, Kruskal-Wallis analysis with Dunn’s test.