Review
Clinician's guide to human papillomavirus immunology: knowns and unknowns

https://doi.org/10.1016/S1473-3099(09)70108-2Get rights and content

Summary

Oncogenic human papillomavirus (HPV) is a common genital infection that has the potential to develop into cervical cancer in some women. This Review summarises current knowledge on the mechanisms of host immunity that help prevent and control HPV infection and the viral factors that exist to avoid immune surveillance. Although most women clear the infection within a few months, the virus induces a shift towards immune tolerance that can facilitate persistence and permit tumorigenesis. Mechanisms used by HPV to avoid immune surveillance and control include infecting only the basal layer of the cervical epithelium, limiting expression of viral proteins until later stages of epithelial differentiation, undergoing non-lytic replication, and downregulating the expression of important receptors on cells of the innate immune system. Furthermore, HPV suppresses the expression of several proinflammatory proteins that are crucial in clearing infection and activating the cytotoxic T lymphocytes involved in killing virus-infected cells. Interestingly, neutralising antibodies, although of uncertain effectiveness in preventing infection or reinfection after natural exposure (prior infection), are highly protective after immunisation with HPV virus-like-particle-based vaccines. Understanding what is known and unknown about the interaction between the immune system and HPV is important in the assessment of the potential contribution of prophylactic vaccination in reducing the incidence of cervical cancer. However, despite our growing understanding, many aspects of the interactions between HPV and the host immune system remain unknown, and this Review draws attention to several of these unresolved issues and their implications.

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

References (79)

  • R Kirnbauer et al.

    Virus-like particles of bovine papillomavirus type 4 in prophylactic and therapeutic immunization

    Virology

    (1996)
  • A Hildesheim et al.

    Risk factors for rapid-onset cervical cancer

    Am J Obstet Gynecol

    (1999)
  • A Maran et al.

    Human papillomavirus type 11 transcripts are present at low abundance in latently infected respiratory tissues

    Virology

    (1995)
  • AC Rodriguez et al.

    Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections

    J Natl Cancer Inst

    (2008)
  • Initiative for Vaccine Research (IVR). Human papillomavirus

  • JM Walboomers et al.

    Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

    J Pathol

    (1999)
  • FX Bosch et al.

    The causal relation between human papillomavirus and cervical cancer

    J Clin Pathol

    (2002)
  • JS Smith et al.

    Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update

    Int J Cancer

    (2007)
  • Human papillomaviruses (vol 90). IARC monographs on the evaluation of carcinogenic risks to humans

    (2005)
  • GM Clifford et al.

    Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis

    Br J Cancer

    (2003)
  • HD Strickler et al.

    Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women

    J Natl Cancer Inst

    (2005)
  • M Stanley

    HPV—a master at avoiding the host's defences

    HPV Today

    (2007)
  • SC Fausch et al.

    Human papillomavirus virus-like particles do not activate Langerhans cells: a possible immune escape mechanism used by human papillomaviruses

    J Immunol

    (2002)
  • TD Culp et al.

    Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells

    J Virol

    (2006)
  • UA Hasan et al.

    TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16

    J Immunol

    (2007)
  • CM Hebner et al.

    Human papillomaviruses target the double-stranded RNA protein kinase pathway

    J Gen Virol

    (2006)
  • LV Ronco et al.

    Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity

    Genes Dev

    (1998)
  • A de Jong et al.

    Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6

    Cancer Res

    (2004)
  • M Clerici et al.

    Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection

    J Natl Cancer Inst

    (1997)
  • JC Steele et al.

    T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

    Br J Cancer

    (2005)
  • TD de Gruijl et al.

    T cell proliferative responses against human papillomavirus type 16 E7 oncoprotein are most prominent in cervical intraepithelial neoplasia patients with a persistent viral infection

    J Gen Virol

    (1996)
  • SH van der Burg et al.

    Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens

    Proc Natl Acad Sci USA

    (2007)
  • SJ Piersma et al.

    High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer

    Cancer Res

    (2007)
  • JW Molling et al.

    CD4(+)CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

    Int J Cancer

    (2007)
  • RP Viscidi et al.

    Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica

    Cancer Epidemiol Biomarkers Prev

    (2004)
  • FV Cromme et al.

    MHC class I expression in HPV 16 positive cervical carcinomas is post-transcriptionally controlled and independent from c-myc overexpression

    Oncogene

    (1993)
  • A Vambutas et al.

    Altered expression of TAP-1 and major histocompatibility complex class I in laryngeal papillomatosis: correlation of TAP-1 with disease

    Clin Diagn Lab Immunol

    (2000)
  • SL Giannini et al.

    Influence of the mucosal epithelium microenvironment on Langerhans cells: implications for the development of squamous intraepithelial lesions of the cervix

    Int J Cancer

    (2002)
  • F Mota et al.

    The antigen-presenting environment in normal and human papillomavirus (HPV)-related premalignant cervical epithelium

    Clin Exp Immunol

    (1999)
  • Cited by (179)

    • The vaginal microbiome: A complex milieu affecting risk of human papillomavirus persistence and cervical cancer

      2022, Current Problems in Cancer
      Citation 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, Immunity
      Citation 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, Vaccine
      Citation 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.

    View all citing articles on Scopus
    View full text