Natural History of HPV Infection across the Lifespan: Role of Viral Latency

Patti E Gravitt, Rachel L Winer, Patti E Gravitt, Rachel L Winer

Abstract

Large-scale epidemiologic studies have been invaluable for elaboration of the causal relationship between persistent detection of genital human papillomavirus (HPV) infection and the development of invasive cervical cancer. However, these studies provide limited data to adequately inform models of the individual-level natural history of HPV infection over the course of a lifetime, and particularly ignore the biological distinction between HPV-negative tests and lack of infection (i.e., the possibility of latent, undetectable HPV infection). Using data from more recent epidemiological studies, this review proposes an alternative model of the natural history of genital HPV across the life span. We argue that a more complete elucidation of the age-specific probabilities of the alternative transitions is highly relevant with the expanded use of HPV testing in cervical cancer screening. With routine HPV testing in cervical cancer screening, women commonly transition in and out of HPV detectability, raising concerns for the patient and the provider regarding the source of the positive test result, its prognosis, and effective strategies to prevent future recurrence. Alternative study designs and analytic frameworks are proposed to better understand the frequency and determinants of these transition pathways.

Keywords: cervical cancer; latency; papillomavirus.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic model of the population-level natural history of human papillomavirus infection and cervical cancer. Purple boxes indicate well-accepted natural history model parameters; blue boxes represent uncertainties.
Figure 2
Figure 2
Schematic model of individual-level natural history of female genital HPV infection across the life span. The model assumes two pathways to type-specific HPV positivity after an HPV-negative test result—new acquisition or reinfection due to current sexual activity, or reactivation/recurrent detection of controlled, latent HPV infection. Red boxes indicate positive HPV molecular test results and green boxes indicate negative HPV molecular test results. Colored fonts represent the true underlying infectious status independent of concurrent molecular test results from exfoliated samples; red = HPV infection, green = HPV uninfected.

References

    1. Bosch F.X., Lorincz A., Munoz N., Meijer C.J., Shah K.V. The causal relation between human papillomavirus and cervical cancer. J. Clin. Pathol. 2002;55:244–265. doi: 10.1136/jcp.55.4.244.
    1. Burchell A.N., Winer R.L., de Sanjose S., Franco E.L. Chapter 6: Epidemiology and Transmission Dynamics of Genital HPV Infection. Vaccine. 2006;24(Suppl. 3):S52–S61. doi: 10.1016/j.vaccine.2006.05.031.
    1. Schiffman M., Castle P.E., Jeronimo J., Rodriguez A.C., Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890–907. doi: 10.1016/S0140-6736(07)61416-0.
    1. Fu T.C., Carter J.J., Hughes J.P., Feng Q., Hawes S.E., Schwartz S.M., Xi L.F., Lasof T., Stern J.E., Galloway D.A., et al. Re-detection vs. new acquisition of high-risk human papillomavirus in mid-adult women. Int. J. Cancer. 2016;139:2201–2212. doi: 10.1002/ijc.30283.
    1. Shew M.L., Ermel A.C., Tong Y., Tu W., Qadadri B., Brown D.R. Episodic detection of human papillomavirus within a longitudinal cohort of young women. J. Med. Virol. 2015;87:2122–2129. doi: 10.1002/jmv.24284.
    1. Liu S.H., Cummings D.A., Zenilman J.M., Gravitt P.E., Brotman R.M. Characterizing the temporal dynamics of human papillomavirus DNA detectability using short-interval sampling. Cancer Epidemiol. Biomark. Prev. 2014;23:200–208. doi: 10.1158/1055-9965.EPI-13-0666.
    1. Carter J.J., Koutsky L.A., Hughes J.P., Lee S.K., Kuypers J., Kiviat N., Galloway D.A. Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J. Infect. Dis. 2000;181:1911–1919. doi: 10.1086/315498.
    1. Gravitt P.E. Evidence and impact of human papillomavirus latency. Open Virol. J. 2012;6:198–203. doi: 10.2174/1874357901206010198.
    1. Strickler H.D., Burk R.D., Fazzari M., Anastos K., Minkoff H., Massad L.S., Hall C., Bacon M., Levine A.M., Watts D.H., et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J. Natl. Cancer Inst. 2005;97:577–586. doi: 10.1093/jnci/dji073.
    1. Fu T.C., Hughes J.P., Feng Q., Hulbert A., Hawes S.E., Xi L.F., Schwartz S.M., Stern J.E., Koutsky L.A., Winer R.L. Epidemiology of Human Papillomavirus Detected in the Oral Cavity and Fingernails of Mid-Adult Women. Sex. Transm. Dis. 2015;42:677–685. doi: 10.1097/OLQ.0000000000000362.
    1. Baay M.F., Francois K., Lardon F., Van Royen P., Pauwels P., Vermorken J.B., Peeters M., Verhoeven V. The presence of Y chromosomal deoxyribonucleic acid in the female vaginal swab: Possible Implications for Human Papillomavirus Testing. Cancer Epidemiol. 2011;35:101–103. doi: 10.1016/j.canep.2010.10.005.
    1. Gravitt P.E. The known unknowns of HPV natural history. J. Clin. Investig. 2011;121:4593–4599. doi: 10.1172/JCI57149.
    1. Theiler R.N., Farr S.L., Karon J.M., Paramsothy P., Viscidi R., Duerr A., Cu-Uvin S., Sobel J., Shah K., Klein R.S., et al. High-risk human papillomavirus reactivation in human immunodeficiency virus-infected women: Risk Factors for Cervical Viral Shedding. Obstet. Gynecol. 2010;115:1150–1158. doi: 10.1097/AOG.0b013e3181e00927.
    1. Rositch A.F., Burke A.E., Viscidi R.P., Silver M.I., Chang K., Gravitt P.E. Contributions of recent and past sexual partnerships on incident human papillomavirus detection: Acquisition and Reactivation in Older Women. Cancer Res. 2012;72:6183–6190. doi: 10.1158/0008-5472.CAN-12-2635.
    1. Maglennon G.A., McIntosh P., Doorbar J. Persistence of viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression. Virology. 2011;414:153–163. doi: 10.1016/j.virol.2011.03.019.
    1. Maglennon G.A., McIntosh P.B., Doorbar J. Immunosuppression facilitates the reactivation of latent papillomavirus infections. J. Virol. 2014;88:710–716. doi: 10.1128/JVI.02589-13.
    1. Winer R.L., Hughes J.P., Feng Q., Stern J.E., Xi L.F., Koutsky L.A. Incident Detection of High-Risk Human Papillomavirus Infections in a Cohort of High-Risk Women Aged 25–65 Years. J. Infect. Dis. 2016;214:665–675. doi: 10.1093/infdis/jiw074.
    1. Gravitt P.E., Rositch A.F., Silver M.I., Marks M.A., Chang K., Burke A.E., Viscidi R.P. A cohort effect of the sexual revolution may be masking an increase in human papillomavirus detection at menopause in the United States. J. Infect. Dis. 2013;207:272–280. doi: 10.1093/infdis/jis660.
    1. Herbenick D., Reece M., Schick V., Sanders S.A., Dodge B., Fortenberry J.D. Sexual behavior in the United States: Results from a National Probability Sample of Men and Women Ages 14–94. J. Sex. Med. 2010;7(Suppl. 5):255–265. doi: 10.1111/j.1743-6109.2010.02012.x.
    1. Mercer C.H., Tanton C., Prah P., Erens B., Sonnenberg P., Clifton S., Macdowall W., Lewis R., Field N., Datta J., et al. Changes in sexual attitudes and lifestyles in Britain through the life course and over time: Findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal) Lancet. 2013;382:1781–1794. doi: 10.1016/S0140-6736(13)62035-8.
    1. Ryser M.D., Rositch A., Gravitt P.E. Age and sexual behavior indicates an increasing trend of HPV infection following the sexual revolution. J. Infect. Dis. 2017;3:46–49.
    1. Strickler H.D., Schiffman M.H., Shah K.V., Rabkin C.S., Schiller J.T., Wacholder S., Clayman B., Viscidi R.P. A survey of human papillomavirus 16 antibodies in patients with epithelial cancers. Eur. J. Cancer Prev. 1998;7:305–313. doi: 10.1097/00008469-199808000-00006.
    1. Carter J.J., Koutsky L.A., Wipf G.C., Christensen N.D., Lee S.K., Kuypers J., Kiviat N., Galloway D.A. The natural history of human papillomavirus type 16 capsid antibodies among a cohort of university women. J. Infect. Dis. 1996;174:927–936. doi: 10.1093/infdis/174.5.927.
    1. Wang S.S., Schiffman M., Herrero R., Carreon J., Hildesheim A., Rodriguez A.C., Bratti M.C., Sherman M.E., Morales J., Guillen D., et al. Determinants of human papillomavirus 16 serological conversion and persistence in a population-based cohort of 10 000 women in Costa Rica. Br. J. Cancer. 2004;91:1269–1274. doi: 10.1038/sj.bjc.6602088.
    1. Ho G.Y., Studentsov Y.Y., Bierman R., Burk R.D. Natural history of human papillomavirus type 16 virus-like particle antibodies in young women. Cancer Epidemiol. Biomark. Prev. 2004;13:110–116. doi: 10.1158/1055-9965.EPI-03-0191.
    1. Gage J.C., Katki H.A., Schiffman M., Fetterman B., Poitras N.E., Lorey T., Cheung L.C., Castle P.E., Kinney W.K. Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection. Int. J. Cancer. 2015;136:1665–1671. doi: 10.1002/ijc.29143.
    1. Safaeian M., Porras C., Schiffman M., Rodriguez A.C., Wacholder S., Gonzalez P., Quint W., Van Doorn L.J., Sherman M.E., Xhenseval V., et al. Epidemiological study of anti-HPV16/18 seropositivity and subsequent risk of HPV16 and -18 infections. J. Natl. Cancer Inst. 2010;102:1653–1662. doi: 10.1093/jnci/djq384.
    1. Ho G.Y., Studentsov Y., Hall C.B., Bierman R., Beardsley L., Lempa M., Burk R.D. Risk factors for subsequent cervicovaginal human papillomavirus (HPV) infection and the protective role of antibodies to HPV-16 virus-like particles. J. Infect. Dis. 2002;186:737–742. doi: 10.1086/342972.
    1. Malik Z.A., Hailpern S.M., Burk R.D. Persistent antibodies to HPV virus-like particles following natural infection are protective against subsequent cervicovaginal infection with related and unrelated HPV. Viral Immunol. 2009;22:445–449. doi: 10.1089/vim.2009.0055.
    1. Schiffman M., Wentzensen N., Wacholder S., Kinney W., Gage J.C., Castle P.E. Human papillomavirus testing in the prevention of cervical cancer. J. Natl. Cancer Inst. 2011;103:368–383. doi: 10.1093/jnci/djq562.
    1. Trottier H., Ferreira S., Thomann P., Costa M.C., Sobrinho J.S., Prado J.C., Rohan T.E., Villa L.L., Franco E.L. Human papillomavirus infection and reinfection in adult women: The Role of Sexual Activity and Natural Immunity. Cancer Res. 2010;70:8569–8577. doi: 10.1158/0008-5472.CAN-10-0621.
    1. Viscidi R.P., Schiffman M., Hildesheim A., Herrero R., Castle P.E., Bratti M.C., Rodriguez A.C., Sherman M.E., Wang S., Clayman B., 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. Biomark. Prev. 2004;13:324–327. doi: 10.1158/1055-9965.EPI-03-0166.
    1. Beachler D.C., Jenkins G., Safaeian M., Kreimer A.R., Wentzensen N. Natural Acquired Immunity Against Subsequent Genital Human Papillomavirus Infection: A Systematic Review and Meta-analysis. J. Infect. Dis. 2016;213:1444–1454. doi: 10.1093/infdis/jiv753.
    1. Velicer C., Zhu X., Vuocolo S., Liaw K.L., Saah A. Prevalence and incidence of HPV genital infection in women. Sex. Transm. Dis. 2009;36:696–703. doi: 10.1097/OLQ.0b013e3181ad25ff.
    1. Xi L.F., Koutsky L.A., Castle P.E., Edelstein Z.R., Hulbert A., Schiffman M., Kiviat N.B. Human papillomavirus type 16 variants in paired enrollment and follow-up cervical samples: Implications for a Proper Understanding of Type-specific Persistent Infections. J. Infect. Dis. 2010;202:1667–1670. doi: 10.1086/657083.
    1. Wheeler C.M., Skinner S.R., Del Rosario-Raymundo M.R., Garland S.M., Chatterjee A., Lazcano-Ponce E., Salmerón J., McNeil S., Stapleton J.T., Bouchard C., et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year Follow-up of the Phase 3, Double-blind, Randomised Controlled Viviane Study. Lancet Infect. Dis. 2016;16:1154–1168. doi: 10.1016/S1473-3099(16)30120-7.
    1. Castellsague X., Munoz N., Pitisuttithum P., Ferris D., Monsonego J., Ault K., Luna J., Myers E., Mallary S., Bautista O.M., et al. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age. Br. J. Cancer. 2011;105:28–37. doi: 10.1038/bjc.2011.185.
    1. Hildesheim A., Herrero R., Wacholder S., Rodriguez A.C., Solomon D., Bratti M.C., Schiller J.T., Gonzalez P., Dubin G., Porras C., et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: A Randomized Trial. JAMA. 2007;298:743–753. doi: 10.1001/jama.298.7.743.
    1. Scherer E.M., Smith R.A., Gallego D.F., Carter J.J., Wipf G.C., Hoyos M., Stern M., Thurston T., Trinklein N.D., Wald A., et al. A Single Human Papillomavirus Vaccine Dose Improves B Cell Memory in Previously Infected Subjects. EBioMedicine. 2016;10:55–64. doi: 10.1016/j.ebiom.2016.06.042.
    1. Polman N.J., Veldhuijzen N.J., Heideman D.A.M., Snijders P.J.F., Meijer C.J.L.M., Berkhof J. HPV-positive women with normal cytology remain at increased risk of CIN3 after a negative repeat HPV test. Br. J. Cancer. 2017 doi: 10.1038/bjc.2017.309.
    1. Franceschi S., Baussano I. Naturally acquired immunity against human papillomavirus (HPV): Why It Matters in the HPV Vaccine Era. J. Infect. Dis. 2014;210:507–509. doi: 10.1093/infdis/jiu143.
    1. Bosch F.X., Robles C., Diaz M., Arbyn M., Baussano I., Clavel C., Ronco G., Dillner J., Lehtinen M., Petry K.U., et al. HPV-FASTER: Broadening the Scope for Prevention of HPV-related Cancer. Nat. Rev. Clin. Oncol. 2016;13:119–132. doi: 10.1038/nrclinonc.2015.146.
    1. Liu S.H., Brotman R.M., Zenilman J.M., Gravitt P.E., Cummings D.A. Menstrual cycle and detectable human papillomavirus in reproductive-age women: A Time Series Study. J. Infect. Dis. 2013;208:1404–1415. doi: 10.1093/infdis/jit337.
    1. Brotman R.M., Shardell M.D., Gajer P., Tracy J.K., Zenilman J.M., Ravel J., Gravitt P.E. Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection. J. Infect. Dis. 2014;210:1723–1733. doi: 10.1093/infdis/jiu330.
    1. Johnston C., Corey L. Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding. Clin. Microbiol. Rev. 2016;29:149–161. doi: 10.1128/CMR.00043-15.
    1. Schiffer J.T., Abu-Raddad L., Mark K.E., Zhu J., Selke S., Koelle D.M., Wald A., Corey L., et al. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proc. Natl. Acad. Sci. USA. 2010;107:18973–18978. doi: 10.1073/pnas.1006614107.

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