ORIGINAL RESEARCH article

Front. Immunol.

Sec. Viral Immunology

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1548814

This article is part of the Research TopicDeciphering Host-Virus Interactions and Advancing Therapeutics for Chronic Viral InfectionView all 4 articles

Wip1 inhibitor CCT007093 alleviates immune exhaustion of lymphocytes via p65 NF-κB and YY1 in chronic hepatitis B virus infection in mice

Provisionally accepted
Yu-Syuan  YouYu-Syuan You1Wan-Ting  ChangWan-Ting Chang1Chia-Lang  HsuChia-Lang Hsu2Hui-Ying  WangHui-Ying Wang1Yan-Fong  LuYan-Fong Lu1,3InKyeom  KimInKyeom Kim4Shiang-Jong  TzengShiang-Jong Tzeng1*
  • 1College of Medicine, National Taiwan University, Taipei, Taiwan
  • 2National Taiwan University Hospital, Taipei, Taiwan
  • 3Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
  • 4Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, North Gyeongsang, Republic of Korea

The final, formatted version of the article will be published soon.

Prolonged viral infections often lead to lymphocyte exhaustion, marked by heightened inhibitory receptor expression like PD-1, compromising host defense mechanisms. The unexplored potential of chemical checkpoint inhibitors in rejuvenating immune responses prompted our investigation. We focused on CCT007093, a Wip1 inhibitor, screened for its distinctive capacity to simultaneously decrease PD-1 and FcγRIIB expression in B cells. In this study, we harnessed a murine model of immune exhaustion induced by chronic hepatitis B virus (HBV) infection using hydrodynamic injection. Treatment with CCT007093 resulted in decreased levels of PD-1 expression, resulting in reduced percentages of PD-1 +/hi CD4 + and CD8 + T cells in circulation, spleen, and liver. The expression levels of PD-1 and FcγRIIB, along with the percentages of PD-1 +/hi and FcγRIIB +/hi CD19 + B cells in these tissues, were similarly diminished. Moreover, intrahepatic lymphocytes treated with CCT007093 displayed heightened responsiveness to ex vivo activation. Consequently, mice treated with CCT007093 exhibited significantly reduced serum HBsAg levels compared to vehicle-treated mice. Our detailed analyses, spanning promoter and transcriptome evaluations, uncovered p65 NF-κB as the primary activator of T cells and B cells, while Ying Yang 1 (YY1) emerged as the key regulator, orchestrating the down-regulation of PD-1 and FcγRIIB gene transcription in response to CCT007093. Our study highlights the prowess of chemical checkpoint inhibitors, exemplified by CCT007093, in alleviating immune exhaustion in HBV-infected mice, particularly by enhancing adaptive immunity.

Keywords: CCT007093, Chronic viral infection, immune exhaustion, Hepatitis B virus (HBV), FcγRIIB, PD-1, Wild-type p53-induced phosphatase (Wip1), Ying Yang 1 (YY1)

Received: 20 Dec 2024; Accepted: 31 Mar 2025.

Copyright: © 2025 You, Chang, Hsu, Wang, Lu, Kim and Tzeng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Shiang-Jong Tzeng, College of Medicine, National Taiwan University, Taipei, 100, Taiwan

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.