Human papillomavirus (HPV) is a small, non-enveloped, double-stranded DNA virus, the most common genital tract virus. More than a hundred HPV genotypes have been identified, of which about 40 are associated with female genital tract infections, and the distinction between HPV types is mainly based on a 291bp fragment located on the L1 ORF gene. Based on the primary site of infection, HPV can be categorized into cutaneous and mucosal types; based on oncogenic potential, HPV viruses are usually categorized into two main groups: high-risk and low-risk types. Low-risk types mainly include HPV6, 11, 30, 42, 43, 44, 61, etc., which often lead to low-grade squamous intraepithelial lesions and benign genital warts. High-risk types mainly include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, which are associated with a variety of malignant tumors, including cervical, vulvar, vaginal, anal, and oropharyngeal cancers in women and penile, anal, and oropharyngeal cancers in men. Among them, HPV 16/18 is the most predominant oncogenic subtype and is associated with about 70% of cervical cancer cases [1].
HPV infection is highly epithelialized, and HPV only selectively infects skin and mucosal epithelial cells. Breaking the skin or mucous membranes is the initiating condition for HPV infection. The sources of HPV infection are mainly patients and virus-infected people. The main ways of transmission of HPV include: (1) Sexual transmission (also the primary means of transmission): mucosal contact during homosexual or heterosexual sex can cause infection; (2) mother-to-child transmission: mothers infected with HPV in the reproductive tract to pass it on to their newborns during labor and delivery, (e.g., recurrent papillomas of the respiratory tract in children may be due to HPV6/11 infection acquired by the child from vaginal secretions during labor and delivery); (3) skin and mucous membrane contact: in addition to the uterine cervix, HPV can also infect other parts of the body: mouth, throat, skin and anus, and induce tumors.
The attributable risk percentage of HPV for cervical cancer can reach 100%, and cervical cancer accounts for the highest proportion of cancers caused by HPV infections globally each year, about 83% [1]. A 1998-2002 study conducted in a county with a high incidence of cervical cancer in Shanxi Province illustrated for the first time found the etiological associations between high-risk HPV infections and cervical cancers and their pre-cancerous lesions (OR values of 135-170 and RR values of 22-355) and the attributable risk percentage (ARP>99%) among the Chinese population. The study confirmed that persistent high-risk HPV infection is a risk factor for cervical cancer in China [2, 3, 4].
Figure 1 depicts the natural course of HPV infection of the uterine cervix. Although the vast majority of HPV infections are asymptomatic transient infections that histologically manifest as low-grade squamous intraepithelial lesions (LSIL) of the uterine cervix, i.e., mild cervical intraepithelial neoplasia (CIN1), the body clears more than 80% of these infections within 6 to 24 months. If the infection persists, it progresses to high-grade squamous intraepithelial lesions (HSIL), i.e., some moderate cervical intraepithelial neoplasia (CIN2) and severe cervical intraepithelial neoplasia (CIN3). More than 60% of CIN1 will improve spontaneously, only about 10% of CIN1 progresses to CIN2 and CIN3 in 2-4 years, and about 1% of CIN1 can progress to cervical cancer [1]. The time it takes to progress from persistent high-risk HPV infection to cervical cancer varies, and the process can take up to ten years or even several decades.
Figure 1. Human papillomavirus lifecycle and organization of its genome.
Young, sexually active women have the highest prevalence of HPV infection in the cervix, with the peak age of infection being around 20 years of age. Although the frequency of HPV infections and the low-grade cervical lesions they cause is high in young women, the vast majority resolve spontaneously within a short period of time, with some women having recurrent infections or being infected with several different types at the same time. Data from large population-based epidemiologic surveys have shown that there is a second peak of HPV infections in women around 40-45 years of age in China, which is associated with a decline in immune function with age and a decrease in the ability to clear new and previous infections in older women [5]. Besides, women with multiple sexual partners or frequent sexual intercourse, women with early sexual debut, women with HPV-infected male sexual partners, women with other sexually transmitted diseases, and immunocompromised people (e.g., HIV-infected patients, AIDS patients, and patients with autoimmune diseases, etc.) are all at high risk for HPV infection.
Risk factors for HPV persistence and progression to cervical cancer include 1) the type of HPV and its tumorigenicity or oncogenicity (e.g., HPV 16 and 18 are the most predominantly oncogenic subtypes and are associated with about 70% of cervical cancer cases); and 2) the individual’s immune status: immunocompromised people are more likely to have persistent HPV infection and develop pre-cancerous lesions and cancers more quickly (in women with normal immune systems, development of cervical cancer can take more than a decade or even decades; while in women with weak immune systems, such as those with untreated HIV infection, it takes only 5 to 10 years; 3) Co-infections with other sexually transmitted pathogens, such as those that cause herpes simplex, chlamydia, and gonorrhea; 4) high number of full-term pregnancies and young age at first pregnancy; and 5) tobacco use [1].
Content Reviewer: Kelly Hunter, Zhangyang Pan
References:
- Wang Huaqing, Zhao Fanghui, Zhao Yun. Expert consensus on immunological prevention of human papillomavirus‑related diseases. Chinese Journal of Preventive Medicine 2019,53(8):761-803.
- Zhang Shaokai, Zhao Fanghui, Qiao Youlin. Development and achievements regarding the prevention and control of cervical cancer in the last 20 years in China. Chinese Journal of Preventive Medicine 2020, 41(6):809-812.
- Zhao Fanghui, Rong Shoude, Qiao Youlin, Li Nan, Wu Lingying, Zhang Xun. Study of the association between human papillomavirus infection and cervical cancer in Xiangyuan county. Chinese Journal of Preventive Medicine 2001, 22(5):375-378.
- Shi J-F, Belinson JL, Zhao F-H, Pretorius RG, Li J, Ma J-F, Chen F, Xiang W, Pan Q-J, Zhang X: Human papillomavirus testing for cervical cancer screening: results from a 6-year prospective study in rural China. American journal of epidemiology 2009, 170(6):708-716.
- Zhao FH, Lewkowitz AK, Hu SY, Chen F, Li LY, Zhang QM, Wu RF, Li CQ, Wei LH, Xu AD: Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: A pooled analysis of 17 population‐based studies. International journal of cancer 2012, 131(12):2929-2938.
