Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Abstract

Human papillomavirus (HPV) is the most prevalent sexually transmitted virus globally. Persistent high-risk HPV infection can result in cervical precancerous lesions and cervical cancer, with 70% of cervical cancer cases associated with high-risk types HPV16 and 18. HPV infection imposes a significant financial and psychological burden. Therefore, studying methods to eradicate HPV infection and halt the progression of precancerous lesions remains crucial. This review comprehensively explores the mechanisms underlying HPV-related cervical lesions, including the viral life cycle, immune factors, epithelial cell malignant transformation, and host and environmental contributing factors. Additionally, we provide a comprehensive overview of treatment methods for HPV-related cervical precancerous lesions and cervical cancer. Our focus is on immunotherapy, encompassing HPV therapeutic vaccines, immune checkpoint inhibitors, and advanced adoptive T cell therapy. Furthermore, we summarize the commonly employed drugs and other nonsurgical treatments currently utilized in clinical practice for managing HPV infection and associated cervical lesions. Gene editing technology is currently undergoing clinical research and, although not yet employed officially in clinical treatment of cervical lesions, numerous preclinical studies have substantiated its efficacy. Therefore, it holds promise as a precise treatment strategy for HPV-related cervical lesions.

Keywords: cervical cancer; cervical preneoplastic lesions; human papillomavirus; pathogenesis; therapy.

FIGURE 1

Life cycle of human papillomavirus. HPV entry to the basal cells, once it enters into the cells, HPV initiates its genome replication, which is mainly dependent on the E1 and E2 proteins; the expression of E6 and E7 contributes to promote host cell replication and prevent apoptosis. With the differentiation of epithelial cells, the HPV capsid proteins L1 and L2 express on the upper epithelial cells and complete the assembly and release of viral particles.

FIGURE 2

Pathogenesis of HPV infection‐related cervical lesion. Under persistent HPV infection, cervical lesion progress from preneoplastic lesions (CINII‐III) to cervical cancer. During this progress, besides immune factors, the cervical cells undergo a series of malignant transformation because of the virus oncoproteins and gene, including malignant proliferation, cellular senescence, apoptosis inhibited, increased cell metastasis and invasion, and HPV genome integration. The contributing factors, such as vaginal dysbiosis and others, work together, leading to the progression of cervical lesion and cervical cancer finally.

FIGURE 3

Therapeutic interventions of HPV‐associated cervical lesion. Traditional therapy of HPV‐associated cervical lesions is surgical treatment combined with radiation or chemotherapy. Up to now, there is no specific drug available for HPV infection. Immunotherapy and gene editing technology is holding the potential to enable precise therapy for cervical cancer in the future. Other nonsurgical treatments, such as photodynamic therapy, cryotherapy, thermocoagulation, and focused ultrasound, are commonly used for cervical precancerous lesions.