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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

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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 1

CRISPR/CAS9–mediated ATG5 disruption led to increased IFN-I signaling in THP cells.

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CRISPR/CAS9–mediated ATG5 disruption led to increased IFN-I signaling in...
THP-1 cells were transduced with lentiviral particles containing sgRNA52 targeting ATG5 or scrambled sgRNA and subsequently incubated with puromycin to isolate stable cell lines. (A) THP-1-sg52 and scrambled control cell lines were incubated for 6 hours in the absence or presence of 10 μM chloroquine (CQ) to block lysosomal degradation. Whole-cell lysates were collected and ATG5 and LC3 expression was analyzed by Western blotting. β-Actin expression was assessed as a protein-loading control for ATG5 (top 2 blots from same gel) and LCI-II (bottom 2 blots from same gel). The LC3-II/actin ratio was analyzed by ImageJ. (B) IFN-β expression was measured in cell-culture supernatant of scrambled control or THP-1 ATG5-sg52 cells with or without cGAMP stimulation. (C) Relative RNA expression level of MX1, IRF7, and OAS in scrambled or THP-1 ATG5-sg52 cells with or without cGAMP stimulation. Data show the mean values of 3–5 independent experiments ± SEM (represented by error bars) *P < 0.05; **P < 0.01, ****P < 0.0001, Kruskal-Wallis with Dunn’s test.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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