The life cycle, natural history, and immunology of human papillomaviruses

Author
Philip E Castle, PhD, MPH
Section Editor
Martin S Hirsch, MD
Deputy Editor
Allyson Bloom, MD
Disclosures: Philip E Castle, PhD, MPH Speakers Bureau: Roche Molecular Systems [cervical cancer (Cobas
HPV test)]; Cepheid [cervical cancer (GeneXpert HPV test)]. Consultant/Advisory Boards: Roche [HPV testing
(Cobas HPV test)]; Cepheid [cervical cancer (GeneXpert HPV test)]; Teva Pharmaceuticals [HPV therapeutics];
Genticel [HPV testing]; ClearPath [HPV testing]; Guided Therapeutics [HPV testing]; Hologic [HPV testing (Aptima
HPV Test)]; GE Healthcare [Sample prep (FTA Elute-specimen transport medium)]. Data and Safety Monitoring
Board: Merck [cervical cancer (Gardasil and Gardasil 9 HPV vaccines)]. Martin S Hirsch, MD Nothing to
disclose. Allyson Bloom, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
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Literature review current through: Jun 2015. | This topic last updated: Apr 17, 2015.
INTRODUCTION Human papillomaviruses (HPV) are highly prevalent, species- and tissuespecific DNA viruses that infect epithelial cells [1,2]. Persistent viral infection with carcinogenic HPV
genotypes causes virtually all cancer of the cervix [3-5]. Carcinogenic HPV infections also cause
many cancers of the anus, vagina, vulva, penis, and oropharynx [6-8].
Cervical cancer is the third most common cancer in women worldwide [5,9]. Although
Pap testing/cytologic screening has reduced the incidence of cervical cancer by 70 percent or more
where it has been effectively implemented, cervical cancer remains a leading cause of death in
countries without effective screening programs [10]. (See"Invasive cervical cancer: Epidemiology,
risk factors, clinical manifestations, and diagnosis".)
Based on the etiologic link between persistent carcinogenic HPV infection of the cervix and cervical
cancer [3,4,11] and its immediate precursor lesions [12], one approach for the prevention of cervical
disease is HPV vaccination [13]. This topic will review the life cycle, natural history and immune
response to HPV and clinical trial data on the efficacy and safety data related to the available
formulations of HPV vaccines. (See "Epidemiology of human papillomavirus
infections" and "Virology of human papillomavirus infections and the link to cancer".)
HPV GENOTYPES Over 40 mucosal HPV genotypes infect the lower female genital tract.
Approximately 15 HPV types can cause all cervical cancer worldwide and are known as
carcinogenic, high-risk, or cancer-associated HPV types [5]. The carcinogenic genotypes of HPV16
and HPV18, which are targeted by the current versions of the HPV vaccine, cause approximately 70
percent of all cervical cancers worldwide [14].
Productive viral infections lead to cervical abnormalities that are classified according to specimen
(eg, cytology or histology) and by severity (eg, mild, moderate, or severe). Mild and morphologic
changes that are the result of production HPV infections are classified as cytologic low-grade

squamous intraepithelial lesion [LSIL] or histologic cervical intraepithelial neoplasia grade 1 [CIN1],
whereas cervical precancerous lesions are classified as cytologic high-grade squamous
intraepithelial lesion [HSIL] or histologic CIN2 or CIN3 [CIN2/3]. (See "Cervical intraepithelial
neoplasia: Terminology, incidence, pathogenesis, and prevention".)
HPV6 and HPV11 cause approximately 90 percent of genital warts or condyloma acuminatum.
It is estimated that targeted HPV protection with the bivalent or quadrivalent vaccine would prevent
approximately half of high-grade precancerous lesions (CIN2 or 3) and 70 percent of invasive
cancers; the quadrivalent vaccine would also prevent most genital warts [15].
HPV LIFE CYCLE HPVs are small, non-enveloped, capsid viruses, with an eight kilobase
circular genome that encodes eight genes including two encapsulating structural proteins, L1 and
L2 [16]. The L1 protein, expressed recombinantly in a cell-culture system, self-assembles in the
absence of the viral genome to form a virus-like particle (VLP). The L1 VLP is the immunogen used
in the HPV vaccines. L2 is the minor capsid protein that along with L1 mediates HPV infectivity
[16,17].
The life cycle of the virus is integrally linked to epithelial differentiation, (ie, the maturation of the
keratinocyte). Initial infection of the basal stem cell occurs as the result of microscopic breaks in the
epithelium [1,18]. The infecting HPV virions appear to attach to the basal stem cell via tissuespecific heparan sulfate proteoglycans [19-21].
Specific gene products are transcribed at every level of differentiation of the squamous keratinocyte
[1]. At the most superficial level, the genes for the L1, L2, and E4 genes are transcribed for
assembly of the viral capsid into which the HPV genome is packaged. Upon desquamation of this
short-lived cell, infectious HPV virions are released for the next round of infection. (See "Virology of
human papillomavirus infections and the link to cancer".)
HPV NATURAL HISTORY A new paradigm of cervical carcinogenesis replaces an older
pathology model of stepwise progression from low-grade to high-grade morphological changes and
can now be summarized as four reliably measured stages:
HPV acquisition
HPV persistence (versus viral clearance)
Progression of a persisting infection to a precancerous lesion
Local invasion
Globally, HPV is the most common sexually transmitted infection. Like all sexually transmitted
infections, peak prevalence of HPV infection typically occurs within the first decade after sexual
debut, typically between the ages of 15 to 25 years in most western countries. A secondary, minor
peak of HPV prevalence has been observed in some populations after menopause, although
neither its cause (eg, new infection or reactivation) nor its clinical importance (eg, malignancy risk)
is understood [5,22]. In China, the prevalence of HPV remains uniformly high at all ages [23]. The
cause of this is unknown. (See "Epidemiology of human papillomavirus infections".)
It has been estimated that at least 50 percent of sexually active women (and men) are exposed to
HPV once in their lifetime [24]. However, many experts believe that virtually all sexually active
adults have been infected by HPV for the following reasons:

Most HPV infections are transient, and can come and go between measures of HPV [2,25]
There are more than 40 HPV types that infect the entire lower genital tract, including the
vagina [18,19,26,27]
Most HPV infections, including carcinogenic HPV genotypes, typically resolve within 6 to 12 months
[25,28]. However, women with persistent carcinogenic HPV infections are at risk of developing
precancerous lesions, although not all persistent infections progress. In the United States, the
median age of cytologically-detected precancerous lesions occurs approximately 10 years after the
median age of sexual debut [29].
There is increasing evidence that HPV can enter a latent state [30,31]. Additionally, there is
evidence of cervical viral reactivation in HIV-infected women and in older women [30,32]. However,
it is unknown whether all or only a subset of HPV infections becomes latent and whether reemergent HPV infections carry a significant cancer risk.
IMMUNE RESPONSE TO HPV A thorough knowledge of what is known and unknown about the
interaction between the immune system and HPV is important in understanding the potential
contribution of immunization in reducing the incidence of cervical cancer [33].
The best evidence to date of the general importance of the immune response in the natural history
of HPV is from data linkage studies of cancer incidence in HIV/AIDSpopulations and solid organ
transplant populations. A recent meta-analysis has shown that there is an elevated risk of HPVattributable cancers in both of these patient populations [34]. The risk of HPV-associated cancers in
HIV-infected patients appears to be inversely related to CD4+ counts and higher levels of HIV RNA.
(See "HIV and women".)
HPV infection evades the immune system through a variety of mechanisms, although the molecular
details remain elusive [5]. Although most women clear the infection within a few months, those who
do not are at risk for development of cervical precancer and cancer. The virus may induce a shift
towards immune tolerance that can facilitate persistence. Some of the proposed mechanisms used
by HPV to avoid immune surveillance include [33]:
Infecting only cells of the basal layer of the cervical epithelium
Limiting expression of viral proteins until later stages of epithelial differentiation,
Virally-mediated suppression of the proinflammatory proteins that activate cytotoxic T
lymphocytes, which assist in killing infected cells.
In women who are found to have prevalent HPV infection and CIN, there appears to be a reduction
in the number and change in the phenotypic distribution of antigen-presenting cells (Langerhans'
cells). Poor helper (CD4) and cytotoxic (CD8) T lymphocyte responses against HPV antigens seem
to be associated with HPV infection and cervical disease. Yet, efforts to identify specific subsets of T
cells responsible for clearance remain inconclusive [35].
Epidemiological studies in diverse populations have shown the human leukocyte antigen
DRB1*1301 is associated with a decrease risk of precancer and cancer [26]. In addition to acquired
immune responses, innate immunity could also have an important role at the mucosal level [27].
SUMMARY AND RECOMMENDATIONS

Persistent viral infection with carcinogenic HPV genotypes causes virtually all cancer of the
cervix. Carcinogenic HPV infections also cause most cancers of the anus, vagina, vulva,
penis, and about a third to a half of the cancers the oropharynx. (See 'Introduction' above.)
The carcinogenic genotypes of HPV16 and HPV18, which are targeted by the current
versions of the HPV vaccine, cause approximately 70 percent of all cervical cancers
worldwide. HPV6 and HPV11 cause approximately 90 percent of genital warts or condyloma
acuminatum. (See 'HPV genotypes' above.)
The L1 protein self-assembles in the absence of the viral genome to form a virus-like particle
(VLP), which is the immunogen used in HPV vaccines. (See 'HPV life cycle' above.)
Most HPV infections, including carcinogenic HPV genotypes, typically resolve within 6 to 12
months. However, women with persistent carcinogenic HPV infections are at risk of developing
precancerous lesions, although not all persistent infections progress. (See 'HPV natural
history' above.)
The importance of the immune response in the natural history of HPV is illustrated by the
increased risk of cancer among immunosuppressed or immunocompromised patient
populations. (See 'Immune response to HPV' above.)
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REFERENCES
1.

Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin
Sci (Lond) 2006; 110:525.

2.

de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology

2004; 324:17.

3.

Muoz N, Bosch FX, de Sanjos S, et al. Epidemiologic classification of human

papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518.

4.

Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary
cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12.

5.

Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer.
Lancet 2007; 370:890.

6.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin
2005; 55:74.

7.

D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and
oropharyngeal cancer. N Engl J Med 2007; 356:1944.

8.

Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and
neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers
Prev 2005; 14:467.

9.

Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality
Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on
Cancer; 2010. http://globocan.iarc.fr (Accessed on April 27, 2012).

10.

Cervix Cancer Screening. IARC Press, 2005.

11.

Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer
screening. N Engl J Med 2003; 348:489.

12.

Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human
papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;
85:958.

13.

Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med
2005; 353:2101.

14.

de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in

invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;
11:1048.

15.

Greer CE, Wheeler CM, Ladner MB, et al. Human papillomavirus (HPV) type distribution
and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin
Microbiol 1995; 33:2058.

16.

Yang R, Yutzy WH 4th, Viscidi RP, Roden RB. Interaction of L2 with beta-actin directs
intracellular transport of papillomavirus and infection. J Biol Chem 2003; 278:12546.

17.

Yang R, Day PM, Yutzy WH 4th, et al. Cell surface-binding motifs of L2 that facilitate
papillomavirus infection. J Virol 2003; 77:3531.

18.

Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest 2006;
116:1167.

19.

Johnson KM, Kines RC, Roberts JN, et al. Role of heparan sulfate in attachment to and
infection of the murine female genital tract by human papillomavirus. J Virol 2009; 83:2067.

20.

Selinka HC, Florin L, Patel HD, et al. Inhibition of transfer to secondary receptors by
heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J
Virol 2007; 81:10970.

21.

Shafti-Keramat S, Handisurya A, Kriehuber E, et al. Different heparan sulfate proteoglycans

serve as cellular receptors for human papillomaviruses. J Virol 2003; 77:13125.

22.

Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human

papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005;
191:1796.

23.

Zhao FH, Lewkowitz AK, Hu SY, et al. Prevalence of human papillomavirus and cervical
intraepithelial neoplasia in China: a pooled analysis of 17 population-based studies. Int J Cancer
2012; 131:2929.

24.
25.

http://www.cdc.gov/std/HPV/STDFact-HPV.htm (Accessed on April 27, 2012).

Plummer M, Schiffman M, Castle PE, et al. A 2-year prospective study of human
papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of
undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 2007;
195:1582.

26.

Wang SS, Hildesheim A. Chapter 5: Viral and host factors in human papillomavirus
persistence and progression. J Natl Cancer Inst Monogr 2003; :35.

27.

Carrington M, Wang S, Martin MP, et al. Hierarchy of resistance to cervical neoplasia

mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.
J Exp Med 2005; 201:1069.

28.

Rodrguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and
implications for clinical focus on persistent infections. J Natl Cancer Inst 2008; 100:513.

29.

Castle PE, Fetterman B, Akhtar I, et al. Age-appropriate use of human papillomavirus

vaccines in the U.S. Gynecol Oncol 2009; 114:365.

30.

Rositch AF, Burke AE, Viscidi RP, et al. Contributions of recent and past sexual partnerships
on incident human papillomavirus detection: acquisition and reactivation in older women. Cancer
Res 2012; 72:6183.

31.

Maglennon GA, Doorbar J. The biology of papillomavirus latency. Open Virol J 2012; 6:190.

32.

Theiler RN, Farr SL, Karon JM, et al. High-risk human papillomavirus reactivation in human
immunodeficiency virus-infected women: risk factors for cervical viral shedding. Obstet Gynecol
2010; 115:1150.

33.

Einstein MH, Schiller JT, Viscidi RP, et al. Clinician's guide to human papillomavirus
immunology: knowns and unknowns. Lancet Infect Dis 2009; 9:347.

34.

Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with
HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;
370:59.

35.

Stanley M. Immune responses to human papillomavirus. Vaccine 2006; 24 Suppl 1:S16.

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