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A Longitudinal Study of Human Papillomavirus 16 L1, E6, and E7 Seropositivity and Oral Human Papillomavirus 16 Infection

Beachler, Daniel C. PhD*; Viscidi, Raphael MD; Sugar, Elizabeth A. PhD*‡; Minkoff, Howard MD§; Strickler, Howard D. MD; Cranston, Ross D. MD; Wiley, Dorothy J. PhD**; Jacobson, Lisa P. ScD*; Weber, Kathleen M. MS††; Margolick, Joseph B. MD; Reddy, Susheel MS‡‡; Gillison, Maura L. MD, PhD§§; D’Souza, Gypsyamber PhD*

doi: 10.1097/OLQ.0000000000000236
Original Study

Background Individuals with human papillomavirus (HPV) infections can develop IgG antibodies to HPV proteins including the L1 capsid and E6 and E7 oncoproteins. Evidence on whether L1 antibodies reduce the risk of cervical HPV infection is mixed, but this has not been explored for oral HPV infections. Antibodies to HPV16’s E6 oncoprotein have been detected in some oropharyngeal cancer cases years before cancer diagnosis, but it is unknown if these antibodies are associated with oral HPV16 DNA.

Methods Enzyme-linked immunosorbent assays tested for serum antibodies to HPV16’s L1 capsid in 463 HIV-infected and 293 HIV-uninfected adults, and for antibodies to recombinantly expressed E6 and E7 oncoproteins to HPV16 in 195 HIV-infected and 69 HIV-uninfected cancer-free participants at baseline. Oral rinse samples were collected semiannually for up to 3 years and tested for HPV DNA using PGMY 09/11 primers. Adjusted Poisson, logistic, and Wei-Lin-Weissfeld regression models were used.

Results Human papillomavirus 16 L1 seroreactivity did not reduce the subsequent risk of incident oral HPV16 infection in unadjusted (hazard ratio, 1.4; 95% confidence interval, 0.59–3.3) or adjusted (adjusted hazard ratio = 1.1; 95% confidence interval, 0.41–3.0) analysis. Antibodies to HPV16 E6 and E7 oncoproteins were detected in 7.6% and 3.4% of participants, respectively, but they were not associated with baseline oral HPV16 DNA prevalence or oral HPV16 persistence (each P > 0.40).

Conclusions Naturally acquired HPV16 L1 antibodies did not reduce the risk of subsequent oral HPV16 infection. Human papillomavirus 16 E6 and E7 seropositivity was not a marker for oral HPV16 infection in this population without HPV-related cancer.

A US study found that naturally acquired human papillomavirus 16 L1 antibodies did not reduce the subsequent risk of oral human papillomavirus 16 acquisition Supplemental Digital Content is available in the article.

From the *Departments of Epidemiology, †Molecular Microbiology and Immunology, and ‡Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; §Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY; ¶Departments of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY; ∥Department of Medicine, University of Pittsburgh, Pittsburgh, PA; **School of Nursing, University of California–Los Angeles, Los Angeles, CA; ††Hektoen Institute of Medicine, The CORE Center at John H. Stroger Jr Hospital of Cook County, Chicago, IL; ‡‡Department of Infectious Disease, Northwestern University, Chicago, IL; and §§Viral Oncology Program, Ohio State University Comprehensive Cancer Center, Columbus, OH

Acknowledgments: The MACS centers in the POPS are funded by the following: U01-AI35042 (Johns Hopkins Bloomberg School of Public Health [JHU]—Margolick), U01-AI35039 (Northwestern University—Wolinsky), and U01-AI35041 (University of Pittsburgh—Rinaldo). The MACS DMAC at JHU is funded by UM1-AI35043 (Jacobson). MACS data collection is also supported by UL1-TR000424 (JHU CTSA). The Women Interagency HIV Study centers in the POPS are funded by the following: U01-AI-031834 (Brooklyn—Minkoff and Gustafson), U01-AI-034993 (Chicago—Cohen), and U01-AI-034993 (Washington—Young). The WIHS DMAC is funded by U01-AI-042590 (Gange and Golub).

G.D., D.C.B., K.M.W., E.A.S., R.D.C., and H.M. have no conflicts of interests to report. R.D.C. and D.J.W. have research support from Merck & Co, Inc. D.J.W. is a member of the speakers bureau for Merck & Co, Inc. M.L.G. has been a consultant for Merck & Co, Inc, and GSK. R.D.C. also reports institutional grant funding and royalties from UptoDate (on human papillomavirus–related topics).

This work was supported by R01 DE021395 and related supplement (principal investigator: G. D’Souza, National Institute of Dental and Craniofacial Research), a supplement to U01-A1-35043 (National Institute of Allergy and Infectious Disease), and by the Oral Cancer Foundation. The lead author was funded through T32 CA CA009314. This work was also partially funded by Johns Hopkins Bloomberg School of Public Health Department of Epidemiology’s Doctoral Student Research Fund.

The data were presented in part during the 2014 International Papillomavirus (IPV) conference in Seattle, Washington.

Correspondence: Gypsyamber D’Souza, PhD, Johns Hopkins Bloomberg School of Public Health, Baltimore, 615 N Wolfe St, E6132B, Baltimore, MD 21205. E-mail:

Received for publication September 22, 2014, accepted December 8, 2014.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (

Human papillomavirus (HPV) 16 is the most commonly detected HPV type in the oral region1,2 and causes most HPV-positive head and neck squamous cell carcinomas.3 Human papillomavirus 16 infections, along with other HPV types, can lead to the production of type-specific antibodies to HPV proteins including to the L1 capsid. These naturally acquired IgG antibodies have been shown to reduce the risk of the subsequent acquisition of cervical HPV infection in some studies,4–8 but not others.9,10 Whether these antibodies impact the subsequent risk of oral HPV infection has not been explored.

Long-term persistent HPV16 infections are known to sometimes lead to the development of antibodies to HPV16’s E6 and E7 oncoproteins, usually late in carcinogenesis.11 E6 antibodies are strongly associated with HPV-positive oropharyngeal cancer12 and have been detected in some cases more than 10 years before their cancer diagnoses,13 but it is unknown if these antibodies are common among cancer-free individuals currently infected with oral HPV16.

Therefore, we examined the relationship between HPV16 L1, E6 and E7 seropositivity and oral HPV16 infection using a longitudinal cohort study of HIV-infected and at-risk HIV-uninfected individuals known to have a higher oral HPV16 prevalence.1

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Study Participants

These analyses included individuals from the Persistent Oral human Papillomavirus Study (POPS), a study nested within the Multicenter AIDS Cohort Study (MACS) of men who have sex with men (MSM) and the Women Interagency HIV Study (WIHS).1,14,15 There were 463 HIV-infected and 293 at risk HIV-uninfected participants who were tested for HPV16 L1 antibodies. These participants met the following criteria: enrolled in 2009 to 2010, not vaccinated with a prophylactic HPV vaccine by study baseline, and had 4 or more POPS follow-up visits. Banked serum was obtained from participant’s baseline POPS visit and tested for HPV L1 antibodies to HPV16 and to the other 2 most common oncogenic oral HPV types in the POPS: HPV33 and HPV45. The detected HPV L1 antibodies may have developed after an HPV infection at any number of anatomic (genital, anal, oral) regions.

Human papillomavirus 16 E6 and E7 antibody testing was performed on a subgroup of 273 participants without a history of any HPV-related cancer (cervical, anal, penile, or oropharyngeal). Participants with a detectable oral HPV16 infection at any POPS visit were included (n = 91), along with twice as many oral HPV16-negative controls (n = 182). These controls were a random sample selected after stratification by cohort and HIV status to match the distribution among oral HPV16-positive individuals. The MACS/WIHS executive committees and the institutional review boards from each site approved the study protocol, and participants provided written informed consent.

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Laboratory Testing

Antibody testing was performed on banked serum samples from participant’s POPS baseline visit by using virus-like particle-enzyme–linked immunosorbent assays (VLP-ELISAs) with HPV16, HPV33, and HPV45 capsids produced in insect cells from recombinant baculoviruses, following previously published methods.16,17 Seropositivty was defined as an optical density (OD) greater than 3 SDs above the mean OD of sera from 2-year-old children.17 For quality assurance, known positive controls were run on each ELISA plate throughout the testing period. When comparing all the samples with duplicates, the intra-assay coefficient of variations (CVs) were 5.8%, 7.4%, and 8.7% for HPV16, HPV33, and HPV45, respectively, whereas the interassay CVs (between different assays plates) were 16.1%, 13.3%, and 23.2% for HPV16, HPV33, and HPV45, respectively.

Banked baseline serum samples were also tested for antibodies to recombinantly expressed HPV16 E6 and E7 oncoproteins. Antibody testing was performed using ELISAs with a microtiter plate with HPV16 E6 and E7 GST-fusion proteins expressed in Escherichia coli according to the protocol of Sehr et al.18 For E6 and E7, the seropositivity cutpoint was defined as an OD greater than 3 SDs above the mean OD of sera of low-risk control cohort of 93 female US army recruits between the ages of 18 and 35 years after excluding positive outliers. Younger females were considered an adequate control population given their very low risk for HPV16 E6 and E7 seropositivity.13 We additionally considered a more stringent cutpoint defined as an OD greater than 5 SDs above the mean OD in the control cohort. When duplicates were compared, the intra-assay CV was 9.3% for E6 and 6.9% for E7.

Oral rinse samples were collected at up to 7 semiannual visits through a 30-second rinse and gargle with Scope mouthwash. DNA was isolated from these samples using a magnetic bead-based automated platform (QIAsymphony SP, Qiagen),19 and then tested for 37 HPV types using the Roche linear array with PGMY09/11 polymerase chain reaction primer pools and reverse line blot hybridization, as previously described.1,19

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Statistical Methods

To compare baseline HPV16 L1 seroprevalence by each risk factor, we used χ2 tests for categorical variables and Mann-Whitney tests for continuous variables. We calculated prevalence ratios (PRs) and 95% confidence intervals (95% CIs) using Poisson regression with robust variance to analyze risk factors associated with baseline HPV16 L1 seroprevalence.

To evaluate the association of baseline L1 antibodies with subsequent risk of infection with the same HPV type, we excluded prevalent oral HPV infections and restricted outcomes to incidently detected infections. We calculated incidence rates and used unadjusted and adjusted Wei-Lin-Weissfeld modeling to evaluate the impact of seropositivity on oral HPV incidence. Seropositivity was also examined by antibody titer level, as titers were a priori categorized into tertiles to match the technique of a previous study.4

For the HPV16 E6/E7 antibody analysis, logistic regression was used to examine whether prevalent oral HPV16 infection was associated with E6 and/or E7 seropositivity at the same visit. Models were adjusted for variables that have been associated with prevalent or incident oral HPV infection.1,20 In different sensitivity analyses for HPV L1, we stratified by sex and HIV status and required 2 negative test results before classifying an infection as “incident.” We also examined the results when restricting to persistent infection (requiring 2 consecutive positive HPV test results) for both the HPV16 L1 and E6/E7 analyses. All statistical tests were 2 sided and considered significant using an α = 0.05 level. All analyses were performed by STATA-MP Version 12.0.

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HPV L1 Seropositivity

Among the 756 eligible participants, there were 167 (22%) who were HPV16 L1 seropositive at baseline. Human papillomavirus 16 L1 seropositivity was similar by age and sex (P > 0.20, Table 1). However, never smoking cigarettes, increased number of recent oral sex partners, and HIV status were all associated with increased HPV16 L1 seroprevalence, even after adjustment for other risk factors (Table 1, all P < 0.05).



Baseline HPV16 L1 seroreactivity did not reduce the subsequent risk of oral HPV16 infection in either unadjusted (hazard ratio [HR], 1.4; 95% CI, 0.59–3.3) or adjusted analyses (adjusted HR [aHR], 1.1; 95% CI, 0.41–3.0; Table 2). Results were similar when restricted to HIV-infected (aHR, 1.0; 95% CI, 0.30–3.5) or HIV-uninfected (aHR, 1.4; 95% CI, 0.27–6.9) individuals, or among only individuals who reported having sex during the study. Results were also similar when requiring 2 consecutive negative test results before the first positive for an infection to be considered incident and when restricting to HPV16 persistent infection as an outcome (data not shown). Although we were underpowered to examine effect modification, we cannot exclude the possibility of an effect of seropositivity on subsequent oral HPV16 infection in certain subgroups such as females (aHR, 0.63; 95% CI, 0.13–3.1), particularly considering seropositive women had a higher HPV16 titer level than did seropositive MSM (OD = 0.51 vs 0.41, P = 0.02).



When stratifying the 167 HPV16 L1–seropositive individuals into antibody titer tertiles, the 55 individuals within the highest tertile had a nonsignificantly lower risk of oral HPV16 infection compared with the L1–seronegative group (aHR, 0.44; 95% CI, 0.05–3.7; Supplemental Table 1, Results also seemed to differ among other HPV types, as HPV33 L1 seropositivity was associated with reduced risk of subsequent oral HPV33 infection (aHR, 0.11; 95% CI, 0.01–0.78; Table 2), whereas HPV45 L1 seropositivity was associated with a higher risk of subsequent oral HPV45 infection (aHR, 3.6; 95% CI, 1.1–11.8; Table 2).

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HPV16 E6 and E7 Seropositivity

Among 195 HIV-infected and 69 at-risk HIV-uninfected participants evaluated, 7.6% (n = 20) were positive for antibodies to the HPV16 E6 oncoprotein, whereas 3.4% (n = 9) were positive for antibodies to the HPV16 E7 oncoprotein. E6 or E7 seropositivity was similar by sex (males vs. females: 8.2% vs. 8.5%, P = 0.94), but was doubled among HIV-infected compared with HIV-uninfected individuals, although the difference was not statistically significant (9.7% vs. 4.4%, P = 0.16).

The prevalences of both HPV16 E6 seroreactivity and HPV16 E7 seroreactivity were similar among individuals with an oral HPV16 infection detected during the POPS compared with those who never had an oral HPV16 infection (Table 3; E6: 10.2% vs. 6.3%, P = 0.25; E7: 4.6% vs. 2.8%, P = 0.47). After adjustment, the odds of E6 and E7 seroreactivity did not statistically differ when comparing those with and without an oral HPV16 DNA detected during POPS (Table 3; E6: adjusted OR, 2.0; 95% CI, 0.55–6.9; E7: adjusted OR, 2.0; 95% CI, 0.52–7.9). Results were also similar and nonsignificant when restricting to oral HPV16 infections detectable at baseline of this study (i.e., prevalent, P = 0.78) and when restricting to oral HPV16 infections persisting at least 6 months (P = 0.58).



When a more stringent seropositivity cutpoint was used (an OD that was 5 SDs above the mean OD in the control cohort), the number of E6 positive individuals declined from 20 to 6 individuals (prevalence, 2.3%), whereas the number of E7-positive individuals declined from 9 to 3 individuals (prevalence, 1.1%). However, there was still no association for either E6 or E7 seropositivity with HPV16 DNA (E6: OR, 1.2; 95% CI, 0.22–6.88; E7: OR, 1.2; 95% CI, 0.11–13.6).

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This study found that HPV16 L1 seropositivity from natural infection did not reduce the subsequent risk of oral HPV16 infection. One potential explanation is that natural immunity may not protect against oral HPV16 infection. In addition, HPV16 E6/E7 seropositivity was not more common among individuals with concurrent oral HPV16 DNA suggesting that, like in cervical cancer, these E6/E7 antibodies may not be induced early in the carcinogenesis process and may not be suitable biomarkers for oral HPV16 infection in populations without HPV-related cancer.

Assessing the existence of naturally acquired (L1) immunity against oral HPV can be useful to evaluate the possible benefit of vaccinating sexually active individuals for HPV.21 Although we did not find evidence that HPV16 L1 seropositivity protects against subsequent oral HPV16 infection, it is unclear whether it may have a differential impact on infection risk at different anatomical sites. Several studies have suggested that HPV16 L1 seropositivity may partially protect against subsequent cervical HPV infection,4–6 but it is unclear if that protection is conferred against HPV at other anatomical sites as 2 other recent studies observed no protection for penile22,23 or anal HPV acquisition in men.23 However, there are several caveats to our finding that HPV16 L1 seropositivity may not impact risk of oral HPV16 infection that need to be considered as the results may differ by population, HPV type, titer level, or assay.

Although our results were similar by HIV status, results in this population may differ from other populations. The incident infections detected in this study may include many reactivated infections as well as some newly acquired infections, as HPV latency has been suggested, especially among immunosuppressed and older individuals.24,25 In addition, we cannot exclude the possibility that HPV16 L1 seropositivity has a different effect on oral HPV16 infection in women than in MSM. Although we had limited power in this study, particularly to examine potential effect modification; differences by sex should be further examined, as a genital HPV study suggested that HPV16 L1 antibodies had no protective effect in men.22

We also cannot preclude the possibility that high titers of HPV16 L1 antibodies may have a protective effect against oral HPV16 infection. A few cervical HPV studies have suggested that protection from naturally acquired antibodies may be stronger among those with higher antibody titers,4,6 and the protective ability of the considerably higher antibody titers induced by the HPV vaccine26 supports this notion. One recent study has suggested that the high titers from the L1-based HPV vaccine may protect against subsequent prevalent oral HPV16, but further examination is needed.27

Although HPV16 L1 seropositivity did not protect against oral HPV16 infection, results differed for the other HPV types examined. Indeed, HPV33 L1 seropositivity was associated with reduced oral HPV33 incidence, whereas HPV45 L1 seropositivity was paradoxically associated with increased HPV45 incidence in this study. Explanations from these incongruities include the following: potential limitations in the assays, residual or unmeasured confounding, or possible actual differences. A previous cervical HPV study also found differences in natural protection by HPV type (protection for HPV16, but no protection for other types such as HPV33 and HPV45).5 Similar to other serologic assays, the VLP-ELISAs used in this study are limited because there are no standard reference serum samples and the assay has been suggested to detect an antibody response for only 50% to 60% of women who previously had detectable cervical HPV DNA.16,28,29 The VLP-ELISA used in this study measured the total type-specific binding IgG antibodies which include both neutralizing and nonneutralizing antibodies. Further research is needed to determine if these results may differ across other serologic assays, particularly those that restrict to neutralizing antibodies.30

This study also observed that HPV16 E6/E7 seropositivity was not associated with concurrent oral HPV16 DNA. Although oral HPV16 DNA and HPV16 E6/E7 seropositivities have both been strongly associated with oropharyngeal cancer,12 this study suggests that the implications of oral HPV16 DNA and E6/E7 seropositivity may be less clear in populations without a diagnosed HPV-related cancer. Although it is unknown whether any participants had undetected oral premalignancies, the lack of an association between E6/E7 seropositivity and persistent oral HPV16 infection supports previous evidence from the cervical cancer field that these oncogenes are not normally expressed until late in the carcinogenesis process.11

Another recent study detected HPV16 E6 antibodies in some oropharyngeal cancer cases more than 10 years before their cancer diagnoses,13 conflicting with what has been seen for cervical cancer.11 Although E6 antibodies have been suggested to have a high specificity for HPV16-positive oropharyngeal cancer,13,31 our ELISA detected HPV16 E6 seroreactivity in 6.3% of our cancer-free participants who did not have an oral HPV16 infection, albeit our population is a higher-risk group. Although specificity may vary depending on the assay, the specificity of a potential HPV16 E6 serologic biomarker in high-risk groups such as HIV-infected individuals would need to be considered in any screening modality.

To our knowledge, this is the first longitudinal study to examine the relationship between HPV16 L1, E6, and E7 serostatus and oral HPV16 infection. This study, coupled with cervical HPV literature,4–6 raises the question of whether the relationship between natural HPV seropositivity and HPV infections at different anatomical sites may vary.

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Supplemental Digital Content

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