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Sexually Transmitted Diseases:
Article

Gender Differences in Sexual Biomarkers and Behaviors Associated With Human Papillomavirus-16, −18, and −33 Seroprevalence

Kreimer, Aimee R. PhD*†; Alberg, Anthony J. PhD*; Viscidi, Rapheal MD‡; Gillison, Maura L. MD, PhD*§

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Author Information

*Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, Bethesda, Maryland; the Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland; and the §Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

This work was supported by grants from the NIDCR (DE13121) and the State of Maryland Cigarette Restitution Fund (MLG). AJA is a recipient of a K07 award (CA73790) from the National Cancer Institute. RV is supported by a grant from the National Institutes of Health (AI-42058). The authors thank the laboratories of Thomas Quinn for performing HIV serologic analysis and Jonathan Zenilman for performing HSV-2 analysis. Maura Gillison is a Damon Runyon-Lilly Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation. The authors also thank Elizabeth Garrett, PhD, from the Department of Biostatistics at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins for guidance with statistical analysis.

Correspondence: Maura L. Gillison, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, G91, Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231. E-mail: gillima@jhmi.edu

Received for publication September 15, 2003,

revised November 26, 2003, and accepted December 11, 2003.

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Abstract

Background: The elevated risk for incident head and neck cancer among human papillomavirus (HPV)-16-seropositive individuals has substantiated a role for HPV in the etiology of head and neck cancers. The relationship between HPV seroreactivity and prevalent oral HPV infection in men and women without cancer has yet to be investigated.

Goal: The goal of this study was to evaluate a possible association between oral HPV infection and HPV seroreactivity after adjustment for gender, sexual behaviors, and sexually transmitted disease.

Study Design: A cross-sectional study of factors associated with HPV-16, −18, and −33 seroreactivity was performed in a population of 586 men and women with and without HIV infection. Antibodies in sera were measured by use of a virus-like protein (VLP)-based enzyme-linked immunosorbent assay. Exfoliated cells from the tonsillar and oral mucosa were analyzed for the presence of 38 mucosal HPV types by polymerase chain reaction.

Results: Women had significantly greater seroreactivity for all HPV types investigated when compared with men (odds ratio, 4.3; 95% confidence interval, 3.0–6.0). Seroprevalence was greatest in men and women aged 35 to 45 years. Tonsillar HPV infection, oral sex with men, and HIV infection were independently associated with HPV seroreactivity in men after adjustment for age and number of sexual partners. In women, HSV-2 seropositivity and a history of sexually transmitted diseases were similarly important. Oral and tonsillar HPV infection were not associated with HPV seroreactivity in women.

Conclusion: HPV seropositivity is associated with sexually transmitted diseases among women and possibly mucosal HPV exposures in men. Tonsillar HPV infection could impact seroprevalence, particularly in men.

HUMAN PAPILLOMAVIRUS (HPV) exposure has traditionally been measured by detection of HPV-induced cytopathologic change, and more recently by HPV DNA detection, in samples collected from the cervix in women and, less frequently, from various anogenital sites in men. However, viral genome detection has limitations as a measure of HPV exposure because only current infection at the specific anatomic site sampled is captured. By contrast, serologic assays using empty viral capsids that preserve conformational epitopes of HPV, or virus-like particles (VLPs), have the potential to capture both time and multiple anatomic sites of infection in a single measure of HPV exposure. 1 Indeed, seroreactivity to HPV-16 VLPs has been associated with risk of incident HPV-associated cancers at both extragenital (oropharyngeal) 2 and anogenital sites. 3

HPV VLP-based assays have been characterized predominantly in seroepidemiologic studies of cervical HPV infection in women. These assays are HPV type-specific 4–6 and highly reproducible. 7 Antibodies to HPV VLPs appear to be stable for up to 13 years, 8–10 although a decline in seroprevalence with age could possibly be explained by waning antibody titers over time. 11–17 Because of the durability of humoral immune responses, HPV seroreactivity has been validated as a marker of past and current HPV exposure. 10,18 HPV seroreactivity has been associated with several measures of lifetime sexual behavior, 19 including a high number of lifetime sexual partners 11–13,15,16,19–22 and years of sexual activity. 13,15

HPV seroreactivity is a complex consequence of HPV exposure and the subsequent immune response. HPV-16 serologic assays have a limit of sensitivity for current cervical HPV DNA infection of approximately 50%. 1,5,12,23,24 The low sensitivity in cross-sectional studies could be partially explained by a prolonged median time to seroconversion following incident HPV infection. 5 However, approximately 40% of heavily exposed women do not seroconvert, 16 and women have consistently higher seroprevalence than men, despite a higher prevalence of risky sexual behaviors reported by men. 13–15,17 This discrepancy in seroprevalence by gender remains an unexplained paradox. Absence of seroconversion despite infection has been ascribed to complex mechanisms of immune evasion by the virus and the absence of systemic spread of virus resulting from restriction of infection to the epithelium. 25,26

The potential impact of anatomic site of infection on seroprevalence has not been specifically evaluated. This study was designed to investigate a possible association between prevalent extragenital HPV infection (in the oropharynx and oral cavity) and seroreactivity to several high-risk HPV types after adjustment for gender, self-reported sexual behaviors, and sexually transmitted disease. Given that extragenital cancers, particularly tonsillar cancer, have been etiologically linked to HPV, 27 it is important to understand the relationship between oral HPV infection and serology.

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Methods

The details of the study methods have been reported previously. 28 Briefly, individuals in Baltimore, Maryland, were recruited from 2001 to 2002 to participate in an oral cancer screening program and cross-sectional study of the prevalence of oral HPV infection. Study sites included a Hispanic community center, a drug rehabilitation program, a medical clinic for HIV-infected individuals, and a community health center in Baltimore. The Institutional Review Board of the Johns Hopkins Bloomberg School of Public Health approved the research protocol.

Behavioral data were collected by self-administered questionnaire (Hispanic community center) or by interview (all other study sites). Subjects were queried about their race/ethnicity and demographic data, sexual behaviors, and tobacco and alcohol use. Sexual behaviors that were recorded included age at coitarche, age at first performing oral sex, the number of recent (prior 12 months) versus lifetime sexual partners through vaginal or oral contact, and those that were casual (defined as “a one-night stand” or “sex with a person you do not know”), same-gender, and opposite-gender partners. Subjects were also queried about a history of sexually transmitted infections (STIs; chlamydia, gonorrhea, syphilis, trichomonas, genital warts), HIV infection, and most recent CD4 cell count if HIV-positive by report. Women were queried about a history of cervical cancer screening (Papanicolaou [“Pap”] smears), including abnormal Pap smears. All study subjects were asked about lifetime use of tobacco and alcohol. Current and former users of tobacco and alcohol were questioned on the age at which use was initiated and ceased, and the average amount used per day.

A blood sample was collected into a non-heparinized Vacutainer tube and serum was separated by centrifugation. All study subjects had a transepithelial brush biopsy of the epithelium overlying the palatine tonsils or tonsillar fossae collected by an otolaryngologist by use of an OralCDx cytobrush (as recommended by the manufacturer, CDx Laboratories, Suffern, NY). 29 For oral rinse specimens, 15 mL sterile saline were swished in the oral cavity for 15 seconds, gargled for 15 seconds, and expectorated into a specimen cup. All samples were transported on ice and stored at −70°C until processing.

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Human Papillomavirus Serology

Sera were tested for antibodies to the oncogenic HPV types most commonly detected in HPV-associated squamous cell carcinomas of the head and neck, 27,30–42 specifically, HPV-16, −18, and −33, in a VLP-based, enzyme-linked, immunosorbent assay (ELISA). 21 HPV VLPs were prepared in Trichoplusia ni (High Five) cells (Invitrogen, Carlsbad, CA) from recombinant baculoviruses expressing the L1 and L2 genes of HPV-16 or −33, or the L1 gene alone of HPV-18, and purified by density gradient ultracentrifugation and column chromatography techniques as described previously. 21

Wells of PolySorp microtiter plates (Nunc, Naperville, IL) were coated overnight at 4°C with 50 ng of VLP protein in phosphate-buffered saline (PBS), pH 7.2, and blocked for 3 hours at room temperature with 0.5% (wt/vol) polyvinyl alcohol (PVA), MW 30,000 to 70,000 (Sigma, St. Louis, MO) in PBS (0.5% PVA). The blocking solution was replaced with PBS and the plates were stored at −20°C until use. Before use and after each incubation step, the plates were washed 4 times with PBS containing 0.05% (vol/vol) Tween 20 (Sigma) in an automatic plate washer (Skanwasher 300, Skatron, Lier, Norway). Serum samples diluted 1:100 in 0.5% PVA were left to react for 1 hour at 37°C. Antigen-bound immunoglobulin (Ig) was detected with peroxidase-conjugated goat antibodies against human IgG (Zymed, San Francisco, CA), diluted 1:4000 in 0.5% PVA 0.0025% Tween 20, 0.8% (wt/vol) polyvinylpyrrolidone, MW 360,000 (Sigma) in PBS. After 30 minutes at 37°C, color development was initiated by the addition of 2,2′-azinobis-(3-ethylbenzthiazoline-6-sulfonate) hydrogen peroxide solution (Kirkegaard and Perry, Gaithersburg, MD). The reaction was stopped after 20 minutes by addition of 1% dodecyl sulfate and absorbance was measured at 405 nm, with a reference wavelength of 490 nm, in an automated microtiter plate reader (Molecular Devices, Menlo Park, CA). The assay cutoff was determined by comparison with the distribution of values obtained for 74 children, ages 2 to 5 years, after excluding outliers. 21 This process was repeated until no further values could be excluded, thereby defining the cutpoint for seropositivity for HPV-16 as an optical density (OD) value greater than 0.053; for HPV-18, greater than 0.046; and for HPV-33, greater than 0.065. Seropositivity was defined as 3 standard deviations above the mean optical density obtained for the negative control sera (excluding outliers). Sera were dichotomized as positive or negative for each antibody.

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Human Papillomavirus DNA Detection

Tonsillar epithelial and oral rinse specimens were pelleted by centrifugation and digested with proteinase K as previously described. 28 HPV DNA was detected by multiplex PCR targeted to the conserved L1 region of the viral genome by use of PGMY09/11 primer pools. 43 Coamplification of the β-globin gene was performed as a positive control for the presence of amplifiable DNA in the specimen. 44 PCR products were denatured in 0.13 N NaOH and hybridized to an immobilized HPV probe array using an extended line-blot assay for genotyping of 38 HPV types, HPV-6, −11, −16, −18, −26, −31, −33, −35, −39, −40, −42, −45, −51, −52, −53, −54, −55, −56, −57, −58, −59, −61, −62, −64, −66, −67, −68, −69, −70, −71, −72, −73, −81, −82 (MM4 and IS39 subtypes), −83, −84 and −89, and β-globin (Roche Molecular Systems, Inc., Alameda, CA). 44,45 Positive controls, consisting of 10 and 100 HPV-16 (SiHa) or HPV-18 (C4–2)-positive cells diluted in a background of HPV-negative cells (K562), and a negative control (K562 cells), were processed in the same manner as oral specimens and were included in each experiment. Samples positive for β-globin were considered of sufficient quality for analysis.

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HIV Serology

Detection of HIV-1 infection was performed as per Centers for Disease Control recommendations. 46 Serum samples were tested for HIV-1 antibodies using Vironostika HIV-1 Microelisa System (BioMerieux, Inc., Durham, NC) according to the manufacturer’s protocol. All samples with reactive ELISA results were subsequently evaluated by use of the Cambridge Biotech HIV-1 Western Blot Kit (Calypte Biomedical Corp., Rockville, MD).

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Herpes Simplex Virus Type 2 Serology

Sera were analyzed for the presence of herpes simplex virus type 2 (HSV-2) antibodies by use of Focus Technologies HerpeSelect-2 ELISA IgG (Cypress, CA). 47

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Statistical Analysis

Individuals were considered HPV-seropositive if OD values were greater than the established cutpoints for positivity (HPV-16 >0.053, HPV-18 >0.046, HPV-33 >0.065). Multiple HPV seropositivity was defined as a dichotomous variable representing seropositivity to HPV-16, −18, or −33. Additionally, type-specific HPV seropositivity was defined individually for each of the 3 types examined. For each type-specific analysis, individuals positive for other HPV types were excluded from the denominator because they could not be considered HPV-seronegative.

Associations among demographic factors, tobacco and alcohol use, and sexual behaviors were evaluated with multiple and type-specific HPV seropositivity. Student t test was used to compare means of continuous variables; the chi-squared test or Fisher exact test was used for categorical variables. Logistic regression models were used to estimate odds ratios (OR) and exact 95% confidence intervals (95% CI) for the associations between exposure variables and HPV seroreactivity. Tests for trend were conducted across ordered groups. Variables important in the gender-stratified univariate analysis based on elevated ORs or P values <0.20, as well as variables considered relevant based on the literature, were evaluated in a multiple logistic regression model. The final model was created by inclusion of variables that remained statistically significant after adjustment for the main exposure variables and potential confounders (eg, age and sexual behaviors), and biologically important variables that did not attain statistical significance. All P values reported are 2-sided and were considered statistically significant at P <0.05.

Several of the sexual behavior variables were determined to be collinear using Pearson’s correlation; therefore, a gender-stratified factor analysis was conducted. 48 Variables considered in the factor analysis were age at vaginal debut, number of vaginal sexual partners in the last year, number of lifetime vaginal sexual partners, number of casual sexual partners in the last year, and number of lifetime casual vaginal sexual partners. By evaluating the uniqueness score of each variable, age at vaginal sexual debut was excluded from further factor analyses for both men and women. The number of factors with eigenvalues greater than 1.5 were retained, which resulted in the use of 1 factor each for men and women to appropriately describe the 4 variables of interest. The gender-specific factors created in this analysis represented recent and lifetime vaginal and casual sexual partners, and were used as surrogate variables to adjust for latent sexual behaviors in the multivariate regression model.

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Results

The demographics of the study population enrolled from 4 community settings are displayed in Table 1. Sera were unavailable for 12 of 598 individuals (2.2%). Therefore, the analysis was restricted to the remaining 586 evaluable individuals. Fifty-eight percent of the population was male. The median age of the study population was 40.4 years. Greater than half of the population was black (55.0%), with the remainder being white (40.9%), both non-Hispanic (23.7%) and Hispanic (17.2%). Sixty-one percent of the population reported their annual family income as $10,000 or less, and 46.4% of the study population did not graduate from high school (Table 1).

Table 1
Table 1
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Multiple HPV seropositivity, defined as seropositive to HPV-16, −18, or −33, was 44.1% (235 of 586). Twelve percent (68 of 586) of the population was concomitantly seropositive to HPV-16, HPV-18, and HPV-33. The HPV seroprevalence was significantly higher in women than in men for each of these HPV types (Fig. 1). Multiple HPV seroprevalence was significantly higher in women (OR, 4.3; 95% CI, 3.0–6.0). In type-specific HPV serologic analysis, the HPV-16 seroprevalence was 42.3% in women and 14.1% among men (OR, 4.5; 95% CI, 3.0–6.6). Similarly, women were significantly more likely to be HPV-18- (seroprevalence: women 42.7%, men 18.8%; OR, 3.2; 95% CI, 2.2–4.7) and HPV-33- (seroprevalence: women 28.9%, men 9.7%; OR, 3.8; 95% CI, 2.4–5.9) seropositive. Seropositivity to 1 HPV type was associated with being seropositive to another. Specifically, HPV-16 seropositivity was significantly increased among HPV-18-seropositive individuals (OR, 4.2; 95% CI, 2.6–6.7) and among HPV-33-seropositive individuals (OR, 9.9; 95% CI, 5.6–17.4) after adjustment for the other HPV type.

Fig. 1
Fig. 1
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An oral HPV infection was detected in the tonsillar or oral rinse specimen of 81 of 586 (13.8%; 95% CI, 11.1–16.9) individuals. An oral infection by HPV-16 or −18 was detected in 18 of 586 individuals, and HPV-33 was not detected. The prevalence of oral HPV infection was greater in men than in women (15.9 vs. 10.2%, P = 0.05). An analysis of the relationship between oral HPV infection and HPV seroreactivity revealed that the presence of an oral HPV infection was not associated with multiple HPV seropositivity (OR, 1.1; 95% CI, 0.7–1.8). However, when stratified by sample type (tonsillar and oral rinse) (Table 2), the presence of a tonsillar HPV infection was associated with multiple HPV seropositivity (OR, 3.1; 95% CI, 1.1–8.4). By contrast, no association of oral HPV infection with HPV seropositivity was observed in oral rinse specimens (OR, 0.9; 95% CI, 0.6–1.6). Despite small sample size, associations of type-specific seroprevalence with type-specific oral HPV DNA detection were investigated; no associations were noted (data not shown).

Table 2
Table 2
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Analysis by Age

HPV seroprevalence differed by age in 10-year categories among men (P = 0.017) and women (P = 0.056) (Fig. 2). Among women, multiple HPV seropositivity significantly increased with age until the 35- to 45-year age category (P for trend = 0.04), at which point seroprevalence decreased with increased age (P for trend = 0.04) (Fig. 2). Although a similar age-related pattern was observed in men (Fig. 2), women had significantly higher HPV seroprevalence than men in each age category (P <0.001).

Fig. 2
Fig. 2
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Analysis by Gender

Sexual behaviors reported by men differed significantly from those reported by women (Table 1). Men were significantly more likely to report behaviors associated with risk of sexually transmitted infection acquisition such as younger age at vaginal sexual debut (P <0.001), >10 lifetime vaginal sexual partners (P <0.001), and >5 vaginal sexual partners in the last 12 months (P <0.001). HSV-2 seroprevalence was significantly higher among women compared with men (women: 66.9%, men: 51.2%; P <0.001). HIV seroprevalence did not differ significantly by gender (P = 0.9).

Associations among variables of interest (eg, HIV serostatus, validated biomarkers of sexual activity, oral HPV DNA, and reported sexual behaviors) and multiple seropositivity, defined as seroreactivity to HPV-16, HPV-18, or HPV-33 are displayed in Table 2. Exposures significantly associated with multiple HPV seropositivity were similarly important in the type-specific analysis (data not shown). Because the HPV seroprevalence differed significantly by gender, men and women were considered separately.

In the univariate analysis among men, seropositivity to HIV (OR, 2.3; 95% CI, 1.4–3.9) and HSV-2 (OR, 1.7; 95% CI, 1.0–2.8) were each associated with multiple HPV seroreactivity (Table 2). In this study, sampling the oral region rather than the genital region assessed prevalent HPV infection. HPV DNA in tonsillar epithelial cells was independently associated with multiple HPV seroreactivity in men (OR, 4.3; 95% CI, 1.3–13.9), despite the low prevalence (3.5%) of HPV DNA in the tonsil. By contrast, HPV DNA from oral rinse specimens was not associated with multiple HPV seropositivity.

Sexual behaviors associated with multiple HPV seropositivity among men included ever having same-gender oral sex (OR, 3.6; 95% CI, 1.7–7.9), more than 10 lifetime casual sexual partners (OR, 1.7; 95% CI, 1.0–2.9), HSV-2 seropositivity and history of STIs. Self-reported sexual behaviors found not to be associated with HPV seropositivity included recent number of sexual partners and several measures of heterosexual oral sex (Table 2). In the multivariate analysis in men, HIV seropositivity (OR, 2.1; 95% CI, 1.2–3.9) and same-sex oral sexual contact (OR, 2.9; 95% CI, 1.2–7.1) were significantly associated with multiple HPV seropositivity after adjustment for age and latent sexual behaviors by use of a factor that represented recent and lifetime vaginal and casual sexual partners (Table 3). The association between HPV DNA in tonsillar epithelial cells and HPV seropositivity was in the direction of increased risk but was not statistically significant (OR, 3.3; 95% CI, 0.9–11.6).

Table 3
Table 3
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In the univariate analysis in women, HSV-2 (OR, 3.6; 95% CI, 2.0–6.2), HIV seropositivity (OR, 2.8; 95% CI, 1.5–5.1), history of STIs (OR, 2.8; 95% CI, 1.6–4.8), greater than 10 lifetime sexual partners (OR, 1.9; 95% CI, 1.0–3.8), and report of ever having casual sex (OR, 2.1; 95% CI, 1.2–3.7) were associated with HPV seroprevalence (Table 2). Among the HIV-seropositive women, self-reported CD4+ cell count less than 200 was moderately associated with multiple HPV seropositivity (OR, 2.3; 95% CI, 0.5–11.8), albeit not significantly (Table 2). Current HPV infection in tonsillar epithelial cells was also not significantly associated with HPV seropositivity in women in this study. However, the association was in the direction of increased risk (OR, 3.4; 95% CI, 0.4–29.7), despite the low prevalence of tonsillar HPV DNA among women (2.4%). Other exposures investigated yet not associated with multiple HPV seropositivity included history of an abnormal Pap smear, recent sexual behaviors, and oral sexual practices. Associations that remained robust in multiple regression analyses in women included HSV-2 serostatus (OR, 3.5; 95% CI, 1.8–6.9) and ever reporting an STI (OR, 2.1; 95% CI, 1.1–4.1) after controlling for age and sexual behaviors using a factor that represented recent and lifetime vaginal and casual sexual partners (Table 3). HIV seropositivity appeared to be associated with HPV seropositivity; however, this finding was not statistically significant (OR, 1.8; 95% CI, 0.9–3.6). Other measures were evaluated but did not significantly affect the associations presented. In particular, HPV DNA in tonsillar epithelial cells was not significantly associated with multiple HPV seropositivity when included in the multivariate model for women (OR, 1.6; 95% CI, 0.2–14.6), and did not impact the associations or the significance of the findings presented in Table 3 (data not shown).

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Discussion

This study extends the findings of prior reports of gender inequality in HPV-16 seroprevalence 13–15,17 to high-risk HPV-18 and −33 seroprevalence. Seroprevalence among men was consistently lower than in women, despite higher self-reported prevalence of sexual behaviors associated with STI acquisition in men, as previously reported. 14 Although studies of genital HPV infection in men are few and complicated by sampling variability, genital HPV DNA prevalence appears quite similar in men and women after controlling for sample quality. 49–54 Differences in seroprevalence could therefore reflect gender differences in factors that influence seroconversion among HPV-infected individuals. It is noteworthy that in this and other studies 55,56 HSV-2 seroprevalence was also markedly higher among women than men (66.7 vs. 51.2%). This finding parallels the discrepancy reported in HPV seroprevalence by gender in this study and others, and suggests there could be common aspects to these sexually transmitted pathogens that might explain this apparent paradox. Toward this end, cross-sectional studies could provide hypothesis-generating data for further evaluation in prospective studies.

HSV-2 seropositivity was significantly associated with multiple HPV seropositivity among women in this and a previous study. 57 HSV-2 seropositivity has been validated as a biomarker for “high-risk” behaviors that place an individual at risk for sexually transmitted disease, in particular, high number of sexual partners. 11–13,15,19–22 Therefore, in our model, HSV-2 seroreactivity could be acting as a surrogate marker for exposure to HPV. The association between HPV seropositivity and a history of sexually transmitted diseases other than HSV-2 could be similarly interpreted. The independent effect of HSV-2 from other STIs in our model is consistent with the hypothesis that different sexually transmitted infections could mark different risk behaviors or dynamics of transmissibility of STIs in the population. 57

The associations observed between a history of STIs and multiple HPV seropositivity in this study did, however, persist after adjustment for sexual behaviors among women in the factor analysis. It is therefore plausible that these epidemiologic associations provide clues to biologic factors that influence HPV seroprevalence. HSV-2 infection has been implicated as a cofactor for HPV-mediated pathogenesis; it has been associated with increased risk of incident cervical HPV infection 58 and of cervical cancer after adjustment for HPV infection and sexual behaviors. 59 HSV-2 has recently been shown to upregulate HPV transcription and enhance HPV replication and integration. 58,60,61 Factors previously associated with risk of disease progression are similarly associated with increased HPV seroprevalence and include persistent cervical HPV DNA, 8,62,63 high HPV viral load, 12 and a diagnosis of low- or high-grade squamous intraepithelial lesions. 4,62,64 Additionally, tissue destruction and inflammation associated with sexually transmitted diseases could enhance HPV antigen presentation among HPV-infected individuals. This could explain why several STIs have been linked to seroprevalence. 12,14,15,17 The possible importance of coincident STIs on HPV seroconversion among HPV-infected individuals has not been adequately evaluated.

Same-gender oral sex was significantly associated with HPV seroprevalence among men in this study and could serve as a surrogate marker for high-risk behaviors that increase risk of HPV exposure in men who have sex with men. Sex among men was significantly associated with HPV seropositivity in a population-based study 15 and was significant after adjustment for number of lifetime sexual partners in high-risk bisexual men. 17 In a population of homosexual men, HPV-16 seroprevalence was elevated among HIV-positive men with a prevalent anal dysplasia, 20 but not among HIV-negative men with anal HPV infection. Given the absence of information about anal sex and oral–anal contacts in this study, we cannot control for potential HPV exposures at these sites that could confound the relationship between oral HPV exposures and HPV seropositivity. However, our data would also be consistent with the hypothesis that HPV exposure at a mucosal site (oral or anal) is more likely to result in HPV seroconversion when compared with nonmucosal sites (genital region) in men. Moreover, our data supports the hypothesis that anatomic site of infection within a particular mucosal region could also be important.

In men, HPV infection of the tonsil, and not of the oral cavity as a whole, was significantly associated with multiple HPV seroreactivity. An important caveat to this finding is that the specific HPV types detected in the tonsil were not necessarily the same type investigated in the serologic analysis. However, seroreactivity to 1 HPV type could serve as a reasonable surrogate for exposure to additional HPV types. 57 The relationship between tonsillar HPV infection and HPV seropositivity could not be explained by prevalence, because the prevalence of HPV infection was significantly lower in the tonsil. For this reason, it is also unlikely that tonsillar HPV infection is merely serving as a marker for HPV infection at another anatomic site not sampled (eg, the genital region). Inflammatory infiltration of the epithelium within the tonsillar crypts, where the basal cell layer prone to HPV infection is uniquely exposed, could enhance HPV antigen presentation at this site. There are no natural history studies of oral or tonsillar HPV infection, and therefore it is not known whether a tonsillar HPV infection is more persistent than oral HPV infection at another site. However, it appears from numerous studies of the role of HPV in head and neck cancer pathogenesis that the tonsillar epithelium is uniquely prone to transformation as a consequence of infection. 27,39

HIV infection has previously been reported to influence HPV seroprevalence. The increased HPV seropositivity previously reported in HIV-seropositive women 65,66 was observed in HIV-seropositive men in this study (OR, 2.1; 95% CI, 1.2–3.9). In a recent study, the higher seroprevalence observed among HIV-positive women 65,66 dissipated after adjustment for cervical HPV DNA and dysplasias, 21 suggesting the difference was the result of a higher prevalence of HPV infection in HIV-positive women. Although the association in this study persisted after adjustment for current tonsillar HPV infection, it would likely diminish after adjustment for current genital HPV infection had genital specimens been collected in this study.

This study demonstrated that there could be an association between extragenital mucosal exposures in men and seropositivity to multiple high-risk HPV types, and highlighted several alternative hypotheses to interpretation of epidemiologic factors associated with HPV seroprevalence in women. The prevalence of oral HPV infection is not insignificant in this and other studies, ranging from 9.2% to 18.6%. 35,67,68 The limited studies to date suggest that concordance is poor between oral and genital infections 69,70 and therefore genital HPV DNA is not an appropriate proxy for oral HPV infection and vice versa. Future prospective studies are necessary to differentiate surrogate markers of HPV exposure from biologically important cofactors for HPV seroconversion and should include analysis of oral/oropharyngeal in addition to penile/cervical, and anal specimens for HPV DNA and coexisting STIs.

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