Ramos Miguel Limbert, Ueha Rumi, Goto Takao, Matsumoto Naoyuki, Kondo Kenji
Department of Otolaryngology and Head and Neck Surgery, The University of Tokyo Hospital, Japan; Department of Otolaryngology - Head and Neck Surgery, Bataan General Hospital and Medical Center, Balanga City, Bataan, Philippines.
Department of Otolaryngology and Head and Neck Surgery, The University of Tokyo Hospital, Japan; Swallowing Center, The University of Tokyo Hospital, Japan.
Auris Nasus Larynx. 2025 Aug;52(4):381-387. doi: 10.1016/j.anl.2025.05.011. Epub 2025 Jun 13.
To describe the pathogenesis of human papillomavirus (HPV) and recurrent respiratory papillomatosis (RRP) caused by HPV6/11, immunologic and oncogenic properties, and currently available treatment strategies and to identify and discuss potential treatment targets that can become new foundations for development of future treatments.
A comprehensive literature search was conducted using PubMed and Google Scholar utilizing search terms which includes "recurrent respiratory papillomatosis" "human papillomavirus" "HPV" "laryngeal papillomatosis" in combination with keywords "physiology" "treatment" "surgery" "adjunct therapy" "antiviral therapy" "gene therapy". No particular inclusion/exclusion criteria and no chronologic limitation were set during the search for studies to be used as references.
RESULTS/DISCUSSION: HPV infection begins with breaches in the epithelial barrier where it gains entry and access to the undifferentiated basal layer keratinocytes where the HPV genome interact with the host cell through the production of viral proteins encoded by the early and late gene regions facilitating viral entry, replication and proliferation. Oncoproteins interfere with host immune surveillance mechanism, promote growth factor signaling, and create a tumor microenvironment resulting in uncontrolled cell proliferation and progression of HPV infection. While high-risk HPV types integrate into the host genome and aggressively promote oncogenesis, low-risk HPV remain superficial with limited oncogenic activity and immune activation which allows avoidance of inflammation induction and cytolysis thereby preventing significant antigen production and facilitates immunosurveillance evasion. The current standard of treatment of RRP is surgical debulking using lasers or cold instruments with or without and adjuvant therapies like antivirals, interferons, VEGF/EGFR inhibitors, and immunomodulators. Novel immunotherapies such as gene therapies and immune checkpoint inhibitors show promising results in boosting immune responses and reducing the frequency of surgical interventions.
The treatment for recurrent respiratory papillomatosis still remains as a challenge due to its high recurrence rates needing repeated surgical and medical intervention attributed to its capability to evade the host immune responses. With the current standard of treatment, advances in the understanding of HPV pathogenesis paved a way for development of new treatment strategies. Understanding the complexities of the cellular and immune mechanisms involved between HPV and the host immune system will provide us with better foundation in identifying potential treatment targets in the future.
描述人乳头瘤病毒（HPV）的发病机制以及由HPV6/11引起的复发性呼吸道乳头状瘤病（RRP）、免疫和致癌特性，以及目前可用的治疗策略，并确定和讨论可成为未来治疗发展新基础的潜在治疗靶点。
使用PubMed和谷歌学术进行全面的文献检索，搜索词包括“复发性呼吸道乳头状瘤病”“人乳头瘤病毒”“HPV”“喉乳头状瘤病”，并结合关键词“生理学”“治疗”“手术”“辅助治疗”“抗病毒治疗”“基因治疗”。在搜索用作参考文献的研究时，未设定特定的纳入/排除标准，也没有时间限制。
结果/讨论：HPV感染始于上皮屏障的破损，它通过破损处进入并接触未分化的基底层层角质形成细胞，在那里HPV基因组通过早期和晚期基因区域编码的病毒蛋白的产生与宿主细胞相互作用，促进病毒的进入、复制和增殖。癌蛋白干扰宿主免疫监视机制，促进生长因子信号传导，并创造肿瘤微环境，导致HPV感染的细胞不受控制地增殖和进展。虽然高危型HPV整合到宿主基因组中并积极促进肿瘤发生，但低危型HPV仍停留在表面，致癌活性和免疫激活有限，这使得它能够避免炎症诱导和细胞溶解，从而防止大量抗原产生并便于逃避免疫监视。RRP目前的治疗标准是使用激光或冷器械进行手术切除，可联合或不联合抗病毒药物、干扰素、VEGF/EGFR抑制剂和免疫调节剂等辅助治疗。新型免疫疗法如基因疗法和免疫检查点抑制剂在增强免疫反应和减少手术干预频率方面显示出有前景的结果。
由于复发性呼吸道乳头状瘤病的高复发率，需要反复进行手术和药物干预，这归因于其逃避免疫反应的能力，因此其治疗仍然是一个挑战。按照目前的治疗标准，对HPV发病机制的深入了解为新治疗策略的开发铺平了道路。了解HPV与宿主免疫系统之间细胞和免疫机制的复杂性，将为我们未来确定潜在治疗靶点提供更好的基础。
