ReviewClinician's guide to human papillomavirus immunology: knowns and unknowns
Introduction
Cervical cancer is a major cause of morbidity and mortality in women worldwide. The DNA of oncogenic human papillomavirus (HPV), the aetiological agent, is detectable in nearly all cervical cancers. Although persistent infection with an oncogenic HPV is thought to be necessary for most cervical tumorigenesis, HPV is very common; the lifetime incidence of cervical infection is estimated to be as high as 80%. However, most infections (even with the most carcinogenic HPV types) have been shown to clear spontaneously, often within a few months.1 Understanding the factors that affect the balance between viral persistence and viral clearance and the role of the immune system in these processes is important. A shift in this balance towards immunity enables most women to clear the infection. A shift towards immune tolerance facilitates persistence and may permit the development of cervical cancer.
The purpose of this review is to summarise current knowledge on the host immune response against infection with HPV, and the mechanisms that HPV uses to avoid immune surveillance and control. This will assist the practising clinician in understanding how HPV infection occurs, why the immune system is sometimes ineffective against genital HPV infections, and how the immune responses generated by prophylactic vaccination differ from the natural host immune responses. We will also draw attention to gaps in our knowledge.
Section snippets
Burden of HPV and cervical neoplasia
Cervical cancer is the second most common cancer in women worldwide, with roughly 500 000 new cases diagnosed and 250 000 cervical cancer deaths in 2007.2 Essentially all cervical cancers contain the DNA of an oncogenic HPV type,3, 4 a common sexually transmitted infection that begins to affect women while they are young, particularly soon after they first engage in sexual intercourse. 40 types of HPV commonly infect the anogenital epithelium, and 15 are thought to be tumorigenic.5 HPV 16 is
Infection and host immune response
The proportion of spontaneous regression that is immune-mediated is unknown, as is the proportion of infected cells that would support viral replication. Nor is it known what fraction of newly detected cervical HPV infections in normal adult women, many of whom are likely to have been previously exposed, represent reactivation of potentially latent infections. Reactivation has commonly been observed in women who are immunosuppressed,9 but its frequency in immunocompetent women remains
Other factors affecting HPV infection or disease
Although discussion of all the factors that affect HPV infection is beyond the scope of this Review, the risk of persistent oncogenic HPV may also be associated with many other factors, such as age, smoking, coinfections with other microorganisms, hormonal status (oestrogen concentrations), oral contraceptive use, and menstruation or menopause.6 Genetic and epigenetic factors are currently being studied for their possible role in cervical tumorigenesis (table 1). Inherited factors may influence
Prophylactic vaccines against oncogenic HPV
The aforementioned findings underscore the mechanisms by which HPV avoids effective recognition by the host immune response. These escape mechanisms have also enabled HPV to become one of the most common sexually transmitted infections worldwide. The development of prophylactic vaccines to prevent oncogenic HPV infection has provided a means to address this issue and potentially prevent the development of cervical cancer. The history of prophylactic papillomavirus vaccination has been reviewed
Relevance for assessing prevention measures
The natural history of HPV is a continuum of exposures to infections, clearance or long-term suppression of infection, and potential latency. Reinfection and re-emergence are possible in women of all ages, but may vary with age or other cofactors. Difficulties remain in assessing the complexities of the antibody response to incident infection or reactivation from latency. As a result, it is unclear how well natural immune responses have induced true clearance of genital oncogenic HPV infection
Conclusion
There are many unique features of HPV infection and the natural host immune response that affect the natural history of the virus and are important to the practising clinician. The immune response required to prevent initial infection in naive women who are vaccinated might be quite different from that which protects women who have cleared initial infection from reinfection. Whereas innate or cell-mediated immune responses could be better suited to fight infection after viral entry into
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Cited by (179)
The vaginal microbiome: A complex milieu affecting risk of human papillomavirus persistence and cervical cancer
2022, Current Problems in CancerCitation Excerpt :HPV evades the immune system to infect the host in multiple ways. First, HPV infection inhibits interferon synthesis, weakening the antiviral immune response.23,25–27 Additionally, HPV replication does not cause cytolysis, necrosis, or viremia as with other viruses; viral proteins are only released in high quantities in terminal cells that are already programmed for cell death, thus evading the typical immune surveillance.28
Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells
2021, ImmunityCitation Excerpt :We were now interested in whether our findings could translate to mucosal tissue and in particular in the ambit of HPV lesions. CXCR3 has been implicated in mucosal anti-viral defenses against HPV (Groom and Luster, 2011), which is an important aspect in HIV disease, as HPV persistence is the key factor for the progression to invasive carcinomas (Einstein et al., 2009; Faber et al., 2020; Kelly et al., 2020; Palefsky, 2009; Poljak et al., 2017). We therefore stained mucosal biopsies from a cohort of HIV+ patients with low nadir (Figure 7A; Table S7) (hereafter referred to as HIVHPV) that presented with histologically confirmed HPV-related anal intraepithelial neoplasia (AIN) and compared the results with HIV– patients with comparable AIN stage (Table S7).
High seroprevalence of multiple high-risk human papillomavirus types among the general population of Bonaire, St. Eustatius and Saba, Caribbean Netherlands
2020, VaccineCitation Excerpt :Human papillomavirus (HPV) is the most common sexually transmitted pathogen in men and women worldwide, approximately infecting 80% of people at some time. Over 200 different HPV genotypes have been identified, of which 40 can infect the genital tract [1]. Persistent infection with high-risk (hr)-HPV types can lead to anogenital- and oropharyngeal cancers, of which cervical cancer is the most prevalent.