Department of Molecular Genetics & Microbiology, The University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
Department of Obstetrics & Gynecology, The University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0151321. doi: 10.1128/AAC.01513-21. Epub 2021 Nov 1.
Human papillomavirus (HPV) infections are transmitted through sexual or other close contact and are etiologically associated with epithelial warts, papillomas, and intraepithelial lesions that may progress to cancer. Indeed, 4.8% of the global cancer burden is linked to HPV infection. Highly effective vaccines protect against two to nine of the most medically important HPV genotypes, yet vaccine uptake is inadequate and/or cost prohibitive in many settings. With HPV-related cancer incidence expected to rise over the coming decades, there is a need for effective HPV microbicides. Herein, we demonstrate the strong inhibitory activity of the heparin-neutralizing drug protamine sulfate (PS) against HPV infection. Pretreatment of cells with PS greatly reduced infection, regardless of HPV genotype or virus source. Vaginal application of PS prevented infection of the murine genital tract by HPV pseudovirions. Time-of-addition assays where PS was added to cells before infection, during infection, or after viral attachment demonstrated strong inhibitory activities on early infection steps. No effect on virus infection was found for cell lines deficient in heparan sulfate expression, suggesting that PS binds to heparan sulfate on the cell surface. Consistent with this, prophylactic PS exposure prevented viral attachment, including under low-pH conditions akin to the human vaginal tract. Our findings suggest PS acts dually to prevent HPV infection: prophylactic treatment prevents HPV attachment to host cells, and postattachment administration alters viral entry. Clinical trials are warranted to determine whether protamine-based products are effective as topical microbicides against genital HPVs.
人乳头瘤病毒 (HPV) 感染通过性或其他密切接触传播，与上皮疣、乳头瘤和可能进展为癌症的上皮内病变有关。事实上，全球 4.8%的癌症负担与 HPV 感染有关。高度有效的疫苗可预防两种至九种最重要的 HPV 基因型，但在许多环境中，疫苗接种率不足且/或费用过高。由于预计未来几十年 HPV 相关癌症的发病率将会上升，因此需要有效的 HPV 杀微生物剂。在此，我们证明了肝素中和药物硫酸鱼精蛋白 (PS) 对 HPV 感染具有很强的抑制活性。PS 预处理细胞可大大降低感染率，而与 HPV 基因型或病毒来源无关。阴道应用 PS 可防止 HPV 假病毒感染小鼠生殖道。添加 PS 的时间加药试验，即在感染前、感染期间或病毒附着后添加 PS，证明对早期感染步骤具有很强的抑制活性。在缺乏硫酸乙酰肝素表达的细胞系中未发现对病毒感染的影响，表明 PS 与细胞表面的硫酸乙酰肝素结合。这与预防性 PS 暴露可预防病毒附着的发现一致，包括在类似于人类阴道的低 pH 条件下。我们的研究结果表明 PS 双重作用以预防 HPV 感染：预防性治疗可防止 HPV 附着到宿主细胞，而附着后给药可改变病毒进入。有必要进行临床试验以确定基于鱼精蛋白的产品是否可作为针对生殖器 HPV 的局部杀微生物剂有效。
