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25-hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling
  • +6
  • Boning Li,
  • Chen Hua,
  • Pu Tian,
  • Yiou Sha,
  • Lu Zhang,
  • Qian Wang,
  • Lu Lu,
  • Shibo Jiang,
  • Long Sui
Boning Li
Obstetrics and Gynecology Hospital of Fudan University
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Chen Hua
Fudan University School of Basic Medical Sciences
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Pu Tian
Obstetrics and Gynecology Hospital of Fudan University
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Yiou Sha
Fudan University School of Basic Medical Sciences
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Lu Zhang
Obstetrics and Gynecology Hospital of Fudan University
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Qian Wang
Fudan University School of Basic Medical Sciences
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Lu Lu
Fudan University School of Basic Medical Sciences
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Shibo Jiang
Fudan University School of Basic Medical Sciences
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Long Sui
Obstetrics and Gynecology Hospital of Fudan University

Corresponding Author:suilong@fudan.edu.cn

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Abstract

Persistent high-risk human papilloma virus (HR-HPV) infection is the main risk factor for cervical cancer, threatening women’s health. Despite growing prophylactic vaccination, annual cervical cancer cases are still increasing and show a trend of younger onset age. However, therapeutic approaches towards HPV infection are still limited. 25-hydrocholesterol (25HC) has a wide-spectrum inhibitory effect on a variety of viruses. To explore efficient interventions to restrict HPV infection at an early time, we applied different pseudoviruses (PsV) to evaluate anti-HPV efficacy of 25HC. We tested PsV inhibition by 25HC in cervical epithelial-derived HeLa and C-33A cells, using high-risk (HPV16, HPV18, HPV59), possibly carcinogenic (HPV73), and low-risk (HPV6) HPV PsVs. Then we established murine genital HPV PsV infection models and applied IVIS to evaluate anti-HPV efficacy of 25HC in vivo. Next, with the help of confocal imaging, we targeted 25HC activity at filopodia upon HPV exposure. After that, we used RNA-seq and Western blotting to investigate 1) how 25HC disturbs actin cytoskeleton remodeling during HPV infection and 2) how prenylation regulates the cytoskeletal remodeling signaling pathway. Our findings suggest that 25HC perturbs F-actin rearrangement by reducing small GTPase prenylation. In this way, the phenomenon of HPV virion surfing was restricted, leading to failed infection.
21 Jan 2023Submitted to Journal of Medical Virology
27 Jan 2023Submission Checks Completed
27 Jan 2023Assigned to Editor
27 Jan 2023Review(s) Completed, Editorial Evaluation Pending
28 Jan 2023Reviewer(s) Assigned
20 Feb 2023Editorial Decision: Revise Major
28 Mar 20231st Revision Received
04 Apr 2023Submission Checks Completed
04 Apr 2023Assigned to Editor
04 Apr 2023Review(s) Completed, Editorial Evaluation Pending
04 Apr 2023Reviewer(s) Assigned
01 May 2023Editorial Decision: Revise Minor
17 May 20232nd Revision Received
17 May 2023Submission Checks Completed
17 May 2023Assigned to Editor
17 May 2023Review(s) Completed, Editorial Evaluation Pending
17 May 2023Editorial Decision: Accept