25-hydroxycholesterol inhibits human papillomavirus infection in
cervical epithelial cells by perturbing cytoskeletal remodeling
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.