Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article AIDS/HIV Inflammation

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

  • Text
  • PDF
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

×

Figure 4

Autophagy inducer rapamycin (Rapa) effectively decreases inflammation and reduces IFN-I signaling.

Options: View larger image (or click on image) Download as PowerPoint
Autophagy inducer rapamycin (Rapa) effectively decreases inflammation an...
(A) At 5.5 weeks after HIV infection, BLT humanized mice were treated with rapamycin or DMSO control for 2 weeks. Afterward, while continuing rapamycin or DMSO treatment, mice were treated with ART for 3.5 weeks, followed by ART interruption for 10 days. (B) HLA-DR and PD-1 expression was measured by flow cytometry (quantitatively by gating of percentages positive) on peripheral blood CD8+ T cells before and after rapamycin or control treatment (n = 5–8 per group) prior to ART. (C) Expression levels of the ISGs MX1, OAS1, and IRF7 in human PBMCs from humanized BLT mice after treatment were measured by real-time PCR throughout HIV-1 infection and from rapamycin- or DMSO control–treated mice in comparison with uninfected animals (n = 5–8 per group). Each dot represents an individual mouse; horizontal bars indicate median values. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, LMM.

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

Sign up for email alerts