For the International Agency for Research on Cancer (IARC) Multicentric Cervical Cancer Study Group
Affiliations of authors: J. S. Smith, N. Muñoz, S. Franceschi, International Agency for Research on Cancer (IARC), Lyon, France; R. Herrero, Proyecto Epidemiológico Guanacaste, Edificio de Residencias Médicas, San José, Costa Rica; C. Bosetti, Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy; F. X. Bosch, X. Castellsagué, Institut Català dOncologia, LHospitalet del Llobregat, Barcelona, Spain; J. Eluf-Neto, Universidade de São Paulo, São Paulo, Brazil; C. J. L. M. Meijer, A. J. C. Van den Brule, Free University Hospital, Amsterdam, The Netherlands; R. Ashley, University of Washington, Seattle.
Correspondence to: Jennifer S. Smith, Ph.D., M.P.H., Unit of Field and Intervention Studies, International Agency for Research on Cancer, 150 Cours Albert Thomas, F-69372 Lyon, France (e-mail: smith{at}iarc.fr).
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ABSTRACT |
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INTRODUCTION |
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Herpes simplex virus type 2 (HSV-2) infection was first considered as a possible causal agent for cervical cancer in the 1960s and 1970s (4,5). Inactivated HSV-2 was shown to transform cells in vitro (6). After HPV DNA was detected in cervical cancer tissue, it was hypothesized that HSV-2 infections might initiate mutations and carcinogenesis in HPV-infected cervical cells (7). The role of HSV-2 in the development of cervical cancer was questioned, however, when HSV-2 DNA was not consistently found in cervical cancer biopsy specimens (8), leading some to propose that HSV-2 acts as a "hit-and-run" agent (9) to cause intracellular changes that do not require the retention of HSV viral genes. Subsequently, molecular evidence from in vitro laboratory data renewed interest in the possible synergism between HPV and HSV-2 infections in the etiology of cervical cancer (10,11). Specifically, in vitro data suggest that the XhoII subfragment of the HSV-2 genome induces the malignant transformation of HPV-immortalized cervical cells and may be retained in cervical cancer tissue (12).
Five casecontrol studies have examined the role of HSV-2 infection in the etiology of invasive cervical cancer by using highly sensitive polymerase chain reaction (PCR)-based assays to detect cervical HPV DNA (1317). One of those studies (13) found a statistically significant association between invasive cervical cancer and HSV-2 seropositivity, after controlling for the presence of HPV DNA, for study subjects from the study site in Spain, but not for those from Colombia (13). When subjects from both locations were tested for the presence of specific subclasses of HSV-2 immunoglobulin G (IgG) antibodies, higher antibody titers of IgG1 were associated with an increased risk of invasive cervical cancer among study subjects in Spain, but not among study subjects in Colombia (14). Two other studies conducted in China (15) and in Honduras (16) that controlled for the presence of specific HPV DNA types found that HSV-2 was not a statistically significant risk factor for invasive cervical cancer. One common limitation of all of these studies, however, is that they used relatively nonspecific serologic assays to distinguish between HSV-2 antibodies (which are almost exclusively associated with genital infections) and HSV-1 antibodies (which are primarily associated with nongenital infections) (18). Although a study from Thailand (17) showed a statistically significant association between invasive cervical cancer and type-specific HSV-2 antibodies after controlling for the presence of HPV DNA detected by PCR, analyses that were restricted to HPV DNA-positive participants were not presented.
To examine the influence of HSV-2 infection as a cofactor of HPV infection in the etiology of invasive cervical cancer, we performed a pooled analysis of seven casecontrol studies of invasive cervical cancer that were conducted in Thailand, the Philippines, Morocco, Peru, Brazil, Colombia, and Spain (1924) using extensive questionnaire data, type-specific HSV-2 serologic testing, and PCR-based assays that detected a wide range HPV viral types.
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SUBJECTS AND METHODS |
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The studies that contributed to this pooled analysis were conducted in seven countries that had different incidences of invasive cervical cancer. Regions covered by these studies include high-incidence populations in Africa [i.e., Morocco (23)] and in South America [i.e., Brazil (20), Peru (24), and Colombia (19)], intermediate-incidence populations in Asia [i.e., Thailand (21) and the Philippines (22)], and a low-incidence population in Spain (19). All studies used similar protocols and questionnaires for subject recruitment and data collection.
The methods that were used and HPV findings that were obtained for each study have already been described (1924). In brief, case patients were eligible for these studies if they had incident, histologically confirmed invasive squamous-cell carcinoma, adenocarcinoma, or adenosquamous-cell carcinoma of the cervix and lived in predefined study areas or were attending the reference hospitals. Case patients had not received previous treatment for cervical carcinoma. Skilled pathologists reviewed the histology slides of the cases of carcinoma and confirmed the diagnoses. Clinical cancer stage was defined according to the International Federation of Gynecology and Obstetrics (25).
Control subjects were population-based for the studies conducted in Spain and Colombia and hospital-based for the studies conducted at the other sites, and all control subjects were frequency-matched to case patients by quinquennium of age. For the hospital-based studies, women were not eligible to participate as control subjects if they had any condition that was related to risk factors for cervical cancer (e.g., neoplasias of the reproductive tract or tobacco-related diseases [i.e., lung cancer or cardiovascular or cerebrovascular diseases]). Only case patients and control subjects for whom HSV-2 serology and HPV DNA laboratory results were available were included in this analysis. Thus, the numbers of case patients and control subjects from each of the seven studies that were included in our study differ from those reported in the original publications. Of the case patients included in our study, 1158 had squamous-cell carcinoma of the cervix and 105 had invasive adeno- or adenosquamous-cell carcinoma of the cervix; 1117 control participants were included.
Personal interviews of study participants were conducted by trained interviewers with the use of a standardized questionnaire that included questions about sociodemographic factors, smoking habits, sexual and reproductive history, history of Pap smear screening, and reported history of sexually transmitted infections.
Women who participated in the seven studies were asked to provide 10 mL of blood for the detection of serum antibodies to HSV-2, HSV-1, and Chlamydia trachomatis. Blood samples were processed by centrifugation at the site of collection. The separated serum was aliquotted, frozen at 20 °C, and shipped to Lyon, France, for storage.
Women who agreed to participate in our study provided written informed consent. All protocols were approved by the Institutional Review Boards of Brazil, Colombia, Morocco, Peru, the Philippines, Spain, Thailand, and the IARC in accordance with the revised Helsinki Declaration of 1983.
HPV DNA Detection
Cervical exfoliated cells were collected from all subjects, processed, and stored as described in the original studies (1924). Cervical biopsy specimens were also obtained from case patients and were kept frozen at 70 °C. Cervical exfoliated cells from control subjects and cervical exfoliated cells or biopsy specimens from case subjects were shipped to central laboratories in Baltimore or Amsterdam, where the HPV DNA testing was performed as detailed below.
Detailed descriptions of the PCR-based hybridization assays, the reference gold standard, that were used to detect HPV DNA are provided in the individual publications of the various studies (1924). Briefly, HPV DNA detection and typing were performed using PCR-based methods to amplify a small fragment of the HPV L1 gene. All PCR assays were performed by laboratory personnel who were blinded to the case or control status of the subjects from whom the samples were obtained. DNA quality was evaluated by amplifying the -globin gene from the same samples by using
-globin gene-specific oligonucleotide primers. For samples from the studies conducted in Colombia and Spain, MY09/MY11 consensus (i.e., broad spectrum) primers were initially used to amplify HPV DNA in the analyses conducted in the central laboratory in Baltimore (19); for samples from the Brazilian study, GP5/6/TS primers (20) were initially used to amplify HPV DNA in the analyses conducted in the central laboratory in Amsterdam. For samples from the remaining studies, GP5+/6+ primers were used to amplify HPV DNA in analyses conducted in the central laboratory in Amsterdam (2023). Ultimately, GP5+/6+ primers (26) were used to test all specimens that were labeled as unknown with respect to HPV type on the basis of results obtained by first using the MY09/MY11 or the GP5/6/TS. PCR products were assessed for HPV DNA positivity by low-stringency Southern blot hybridization using HPV type-specific DNA probes (27). For those samples that were positive for HPV DNA by hybridization, the genotype of the HPV species was determined by Southern blot hybridization using oligonucleotide probes that were specific for 37 different HPV types (HPV 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 66, 68, 70, 71, 72, 73, IS39, MM4, MM7, MM8, CP6108, CP8304, and W13b). HPV DNA-positive specimens that did not hybridize with any of the 37 specific probes were called HPV X. Because the integration of HPV DNA in cervical carcinoma can entail disruption of PCR primer sequences or loss of the HPV L1 open reading frame, we used oligonucleotide primers specific for 100 base pairs in the E7 open reading frame of the 14 high-risk HPV types (i.e., HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) to reamplify specimens from all case patients who were both positive for
-globin amplification and classified as either HPV X or HPV DNA-negative as well as specimens from a sample of control subjects who were
-globin-positive and HPV DNA-negative as previously described (2).
HSV-2 IgG Antibody Detection
Serologic testing for the presence of antibodies to HSV-2 was performed at the University of Washington (Seattle) by individuals who were blinded to case or control status of subjects who provided the blood samples. The University of Washington Virology Laboratory (Seattle, WA) HSV western blot analysis, the reference gold standard (28,29), was used to detect type-specific HSV-2 and HSV-1 antibodies in sera obtained from subjects who lived in Thailand, Morocco, Peru, Colombia, and Spain. To improve the specificity of previously presented findings (13), updated type-specific HSV-2 serology results from the retesting of sera from the Spain and Colombia study with the western blot are included in this article.
Sera collected from subjects who lived in Brazil and the Philippines were screened for HSV-2 IgG antibodies by using the Gull/Pre-Meridian HSV-2 enzyme-linked immunosorbent assay (ELISA; Gull Laboratories, Salt Lake City, UT), according to the manufacturers instructions. All sera with positive, equivocal, or borderline negative ELISA results were retested with the western blot assay to obtain HSV-2 type-specific results (30).
C. trachomatis Antibody Detection
Type-specific serum IgG antibodies to C. trachomatis were detected with the use of a micro-immunofluorescence assay that used purified elementary bodies of C. trachomatis serovar A and pooled serovars BDE, CJHI, and FGK (31). Purified elementary bodies of Chlamydia pneumoniae and Chlamydia psittaci were included in the antigen panel to determine whether the sera contained cross-reactive antibodies to those organisms.
Statistical Analysis
Unconditional logistic regression models were fitted to individual data, and the association between HSV-2 seropositivity and invasive cervical cancer was assessed with likelihood ratio tests (32). To examine the association between HSV-2 and squamous-cell invasive cervical cancer, we first performed separate analyses for each study center. The data from all centers were then pooled for a combined analysis. We present only the results from the pooled analysis for the association between HSV-2 seropositivity and adeno- or adenosquamous-cell carcinomas because of the limited number of case patients that had these diagnoses. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were computed from the unconditional logistic regression models, which included, as indicated, terms for age (in 5-year categories), study center, history of Pap smear screening (ever versus never), oral contraceptive use (never, <5 years of use, 5 years of use), number of full-term pregnancies (0, 12, 34,
5), C. trachomatis seropositivity (seronegative versus seropositive), the number of lifetime sexual partners (
1, 2,
3), and age at first sexual intercourse (younger than 17 years, 1720 years, 21 years or older). Subjects with missing values were excluded from statistical analyses. HPV DNA positivity was considered as a categorical variable by HPV type (HPV-negative; HPV type 16; high-risk HPV types other than HPV 16; HPV types other than high-risk HPV types, including low-risk HPV types or HPV X) and was included in models that were adjusted for HPV positivity or were restricted to HPV-positive women. Because only a few women used injectable contraceptives, women who reported previous hormonal contraceptive use were all considered to be oral contraceptive users (3).
Tests for linear trends of ORs were performed by assigning an increasing score for each level of the categorized variable and fitting the scores in the model as a continuous variable. To test for heterogeneity among the study centers, the difference between the log likelihood of the model that considered the interaction between centers and the exposure of interest and the log likelihood of the model that included the main effects only was compared to the chi-square distribution with degrees of freedom equal to the number of centers minus one. All P values reported are from two-sided tests.
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RESULTS |
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Among the 1048 HPV DNA-positive case patients with squamous-cell invasive cervical cancer for which the clinical stage of invasive cervical cancer was known, the OR for those with stage I and/or II cancers (adjusted OR = 2.5, 95% CI = 1.5 to 4.1) was similar to the OR for those with stage III and/or IV cancers (adjusted OR = 2.4, 95% CI = 1.4 to 4.0) (data not shown). The association between HSV-2 serum antibodies and squamous-cell invasive cervical carcinoma in HPV DNA-positive women did not change after adjustment for the presence of either single or multiple HPV infections (OR for all squamous-cell invasive cervical cancer = 2.19, 95% CI = 1.41 to 3.40) (data not shown). Results of analyses restricted to HPV DNA-positive women that did not control for HPV type were similar to those presented in Fig. 1: the OR for squamous-cell cancer was 2.0 (95% CI = 1.3 to 3.0), and the OR for adeno- or adenosquamous-cell cancer was 2.6 (95% CI = 1.3 to 5.3) (data not shown).
We also examined the effect of HSV-2 seropositivity on the risk of invasive cervical cancer among all case patients and control subjects after adjusting for HPV DNA positivity and other confounders (Fig. 2). The results of those analyses were similar to the results presented in Fig. 1
for the HPV DNA-positive women. HSV-2 seropositivity was associated with statistically significant increased risks of squamous-cell invasive cervical cancer (OR = 1.72, 95% CI = 1.21 to 2.44) and adeno- or adenosquamous invasive cervical cancer (OR = 2.43, 95% CI = 1.22 to 4.81); there was no statistically significant heterogeneity between study centers for either squamous-cell (P = .51) or adeno- or adenosquamous (P = .57) invasive cervical cancer (Fig. 2
). In the model that further adjusted for the number of sexual partners and age at first intercourse, the association between HSV-2 seropositivity and squamous-cell invasive cervical cancer remained statistically significant (OR = 1.9, 95% CI = 1.2 to 3.1) with no statistically significant heterogeneity between study centers (P = .16) (data not shown). In the model that adjusted for all other confounders except HPV DNA positivity, the OR for HSV-2 seropositivity and squamous-cell invasive cervical cancer was 1.9 (95% CI = 1.2 to 3.1) (data not shown).
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DISCUSSION |
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The initial epidemiologic evidence that suggested that HSV-2 infection is a potential etiologic factor for invasive cervical cancer was based on data that compared HSV-2 seropositivity among cases patients and control subjects that did not adequately take into account HPV infection (34). Three casecontrol studies of invasive cervical cancer that did control for the presence of HPV serum antibodies reported ORs of 2.2 (95% CI = 1.1 to 4.5) (35), 1.4 (95% CI = 0.81 to 2.4) (36), and 1.2 (95% CI = 0.8 to 1.8) (37). However, because those ORs were adjusted for HPV seropositivity, residual confounding from HPV infection may be expected in those studies. Indeed, a proportion of the women who are HPV DNA-positive, including approximately 50% of those with invasive cervical cancer (38), might have no detectable HPV antibodies in their serum. Although a large casecontrol study of invasive cervical cancer in Latin America reported an OR of 1.5 (95% CI = 1.2 to 1.9) for those who were HSV-2 seropositive, HPV infection in that study was detected using an in situ hybridization assay that is less accurate than the PCR-based assay used in our study (39). A nested casecontrol study found no association between HSV-2 seropositivity and invasive cervical cancer in 27 patients with invasive cervical cancer and 45 patients with carcinoma in situ after controlling for HPV-16 serum antibodies (OR = 0.6, 95% CI = 0.2 to 1.4) (40). The western blot reference standard for HSV-2 antibody detection was used in only one of these studies (37), thus limiting the ability of these studies to specifically distinguish between HSV-2 and HSV-1 antibody responses.
Our results confirm those of another study (41) that showed that HSV-2 seropositivity is a reliable marker of past sexual behavior. It is thus difficult to determine from previous studies whether HSV-2 is a true etiologic factor or whether the association between HSV-2 serum antibodies and invasive cervical cancer is due to a residual effect of HPV infection or other sexually transmitted infections. In our pooled analysis of invasive cervical cancer, the association between HSV-2 seropositivity and invasive cervical cancer was not substantially reduced when we additionally adjusted for a womans reported number of lifetime sexual partners and her age at first sexual intercourse. Conversely, our results indicate that a womans reported number of lifetime sexual partners is not an independent risk factor for invasive cervical cancer after allowance for HPV and HSV-2 infections. The effect of HSV-2 was consistent in strata of number of lifetime sexual partners and C. trachomatis infection (42), providing further evidence that the effect of HSV-2 may not represent exposure to other sexually transmitted infections. Thus, the effect of HSV-2 ascertained here is unlikely to represent either a surrogate marker of HPV infection or a womans sexual behavior.
Type-specific HSV-1 antibodies, which primarily represent a womans past exposure to nongenital infections, were, unlike HSV-2 antibodies, not associated with an increased risk of squamous-cell invasive cervical cancer in our study. Although we found no statistically significant heterogeneity between study centers, it is worth noting that HSV-2 seropositivity was more strongly associated with an increased risk of invasive cervical cancer in countries where HSV-2 seroprevalence was below 10% among women in the control group (i.e., Spain and the Philippines) than in countries where HSV-2 seroprevalence was greater than 40% among women in the control group (i.e., Colombia and Brazil).
HSV-2, like HPV, can infect cervical squamous epithelial tissue in the squamocolumnar junction, where invasive cervical cancer arises. It has been estimated that concomitant herpetic cervicitis is present in 70%90% of first-episode HSV-2 infections and in 12%20% of recurrent external genital lesions (43). Ulcerative herpetic lesions may serve as HPV cofactors by facilitating the access of HPV to the basal cell layer. Alternatively, inflammatory responses induced by herpetic infections may interfere with a womans ability to mount an effective immune response to HPV infection by suppressing a womans T helper cell-mediated immune response (44), or they may increase the risk of cervical carcinogens by inducing the production of nitric oxide that may result in cellular DNA damage in HPV-infected cells (45). HSV-2 infection may also increase the risk that an oncogenic HPV infection will progress to cervical neoplasia, possibly by increasing HPV replication or the integration of HPV DNA sequences in infected host cells (46). Although HSV DNA or proteins have not been consistently detected in cervical tumors (47), it is possible that HSV may act on host cellular DNA by a hit-and-run mechanism. Further in vitro studies are required to examine whether HSV-2 infection increases HPV viral load or whether HSV-2 infection is capable of transforming human cervical cells that are infected by high-risk HPV types.
Our study has several strengths. It is the largest study to investigate the association between HSV-2 infection and invasive cervical cancer and one of the few to ascertain a broad range of HPV types and to incorporate type-specific serologic testing to detect previous HSV-2 infection. To our knowledge, only one other study (17) used type-specific HSV-2 serologic testing and PCR to detect HPV DNA; however, that study did not show separate results for HPV DNA-positive participants as did our study.
This study also has several potential limitations. First, the use of hospital-based control subjects at five of the study sites may have led to biased results if HSV-2 seroprevalence among those control subjects was not representative of the prevalence among the population source of the invasive cervical cancer case patients. Control participants from those five study sites, however, had a wide range of diagnoses and were ascertained in large, tertiary public hospitals that had wide reference populations (2024), thus reducing the possibility of any substantial selection bias. All invasive cervical cancer case patients in our study were also newly diagnosed and had not been treated previously for invasive cervical cancer, and the frequency of HSV-2 seropositivity among the case patients did not vary by the clinical stage of invasive cervical cancer. A second potential limitation is that human immunodeficiency virus (HIV) antibodies were not evaluated in our study. However, the prevalence of HIV among middle-aged women (median ages between 43 and 56 years) in the study years in the participating countries was expected to be very low (48).
Our decision to analyze HPV DNA-positive participants separately, albeit justified by the causal link between HPV infection and the development of invasive cervical cancer (2), did not alter the relationship between HSV-2 seropositivity and invasive cervical cancer risk. HSV-2 seropositivity was not associated with HPV DNA-positivity among control participants, and the association between HSV-2 and invasive cervical cancer among all study participants was consistent with that among HPV-positive women.
Any interpretation of our study findings must consider issues related to the detection of cervical HPV infection in study participants. Persistent HPV infections have been shown to increase the risk of the progression of an HPV infection to cervical dysplasia (49). Because there is currently no reliable marker of persistent HPV infection, casecontrol studies have the limitation that one cross-sectional measurement of HPV infection cannot distinguish between transient and persistent infections. To increase the likelihood of examining an effect of HSV-2 infection among persistent HPV carriers, some analyses have been limited to women who are all HPV DNA-positive for high-risk HPV types, which are more likely to represent persistent infections than are nononcogenic HPV types (50). The association between HSV-2 seropositivity and risk of squamous-cell carcinoma among women who were HPV DNA-positive for high-risk types was similar to that among HPV DNA-positive women. HPV DNA detection, however, has a different meaning among case patients and control subjects. Among case patients, HPV DNA positivity should indicate a persistent HPV infection, whereas some control subjects may have a transient HPV infection or have been previously infected with HPV in the past and have cleared their infection. Given that the ascertainment of overall HPV prevalence and the relative distribution of HPV types may be differential by case or control status, we controlled for HPV positivity in stratified categories by HPV type (HPV 16, high-risk HPV types other than HPV 16, or other HPV types).
In conclusion, the results of our pooled analysis suggest that although HSV-2 infection may act in conjunction with HPV infection to increase the risk of invasive cervical cancer, the effect of HSV-2 infection on invasive cervical cancer risk is modest compared with the strong effect of HPV infection on invasive cervical cancer risk. Future studies are needed to elucidate at which step in the pathogenesis of HPV-induced cervical carcinogenesis HSV-2 infection may be relevant.
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APPENDIX |
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NOTES |
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We are indebted to all the study participants; to the gynecologists, pathologists, and oncologists who facilitated the identification and contribution of the participants; and to the supervisors of field work. We thank Dr. Keerti Shah, Dr. Kenrad Nelson, and Dr. Johnathan Zenilman for their contributions to the conception of the study and review of the manuscript; Anne Cent for the HSV-2 serologic laboratory work; Annie Arslan for data management; and Y. Guy for the handling of the serum specimens.
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REFERENCES |
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1 International Agency for Research on Cancer (IARC) Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 64. Lyon (France): IARC; 1995.
2 Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:129.[Medline]
3 Moreno V, Bosch FX, Muñoz N, Meijer CJ, Shah KV, Walboomers JM, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002;359:108592.[Medline]
4 Rawls WE, Tompkins WA, Figueroa ME, Melnick JL. Herpesvirus type 2: association with carcinoma of the cervix. Science 1968;161:12556.[Medline]
5 Muñoz N, de-Thé G, Aristizabal N, Yee C, Rabson A, Pearson G. Antibodies to herpesviruses in patients with cervical cancer and controls. In: de-The G, Epstein MA, zur Hausen H, editors. Oncogenesis and herpesviruses II. IARC Sci Publ No. 11. Lyon (France): IARC; 1975. p. 4551.
6 Macnab JC. Transformation of rat embryo cells by temperature-sensitive mutants of herpes simplex virus. J Gen Virol 1974;24:14353.[Medline]
7 zur Hausen H. Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events? Lancet 1982;2:13702.[Medline]
8 Park M, Kitchener HC, Macnab JC. Detection of herpes simplex virus type-2 DNA restriction fragments in human cervical carcinoma tissue. EMBO J 1983;2:102934.[Medline]
9 Galloway DA, McDougall JK. The oncogenic potential of herpes simplex viruses: evidence for a hit-and-run mechanism. Nature 1983;302:214.[Medline]
10 Jones C. Cervical cancer: is herpes simplex virus type II a cofactor? Clin Microbiol Rev 1995;8:54956.[Abstract]
11 DiPaolo JA. The role of Herpes Simplex 2 in the development of HPV-positive cervical carcinoma. Papillomavirus Rep 1999;10:17.
12 DiPaolo JA, Woodworth CD, Coutlee F, Zimonic DB, Bryant J, Kessous A. Relationship of stable integration of herpes simplex virus-2 Bg/II N subfragment Xho2 to malignant transformation of human papillomavirus-immortalized cervical keratinocytes. Int J Cancer 1998;76:86571.[Medline]
13 de Sanjose S, Munoz N, Bosch FX, Reimann K, Pedersen NS, Orfila J, et al. Sexually transmitted agents and cervical neoplasia in Colombia and Spain. Int J Cancer 1994;56:35863.[Medline]
14 Munoz N, Kato I, Bosch FX, de Sanjose S, Sundquist VA, Izarzugaza I, et al. Cervical cancer and herpes simplex virus type 2: case-control studies in Spain and Colombia, with special reference to immunoglobulin-G sub-classes. Int J Cancer 1995;60:43842.[Medline]
15 Peng HQ, Liu SL, Mann V, Rohan T, Rawls W. Human papillomavirus types 16 and 33, herpes simplex virus type 2 and other risk factors for cervical cancer in Sichuan Province, China. Int J Cancer 1991;47:7116.[Medline]
16 Ferrera A, Baay MF, Herbrink P, Figueroa M, Velema JP, Melchers WJ. A sero-epidemiological study of the relationship between sexually transmitted agents and cervical cancer in Honduras. Int J Cancer 1997;73:7815.[Medline]
17 Thomas DB, Qin Q, Kuypers J, Kiviat N, Ashley RL, Koetsawang A, et al. Human papillomaviruses and cervical cancer in Bangkok. II. Risk factors for in situ and invasive squamous cell cervical carcinomas. Am J Epidemiol 2001;153:7329.
18 Ashley RL, Cent A, Maggs V, Nahmias A, Corey L. Inability of enzyme immunoassays to discriminate between infections with herpes simplex virus types 1 and 2. Ann Intern Med 1991;115:5206.[Medline]
19 Munoz N, Bosch FX, de Sanjose S, Tafur L, Izarzugaza I, Gili M, et al. The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. Int J Cancer 1992;52:7439.[Medline]
20 Eluf-Neto J, Booth M, Munoz N, Bosch FX, Meijer CJ, Walboomers JM. Human papillomavirus and invasive cervical cancer in Brazil. Br J Cancer 1994;69:1149.[Medline]
21 Chichareon S, Herrero R, Munoz N, Bosch FX, Jacobs MV, Deacon J, et al. Risk factors for cervical cancer in Thailand: a case-control study. J Natl Cancer Inst 1998;90:507.
22 Ngelangel C, Munoz N, Bosch FX, Limson GM, Festin MR, Deacon J, et al. Causes of cervical cancer in the Philippines: a case-control study. J Natl Cancer Inst 1998;90:439.
23 Chaouki N, Bosch FX, Munoz N, Meijer CJ, El Gueddari B, El Ghazi A, et al. The viral origin of cervical cancer in Rabat, Morocco. Int J Cancer 1998;75:54654.[Medline]
24 Santos C, Munoz N, Klug SJ, Almonte M, Guerrero I, Alvarez M, et al. HPV types and cofactors causing cervical cancer in Peru. Br J Cancer 2001;85:96671.[Medline]
25 Evander M, Edlund K, Gustafsson A, Jonsson M, Karlsson R, Rylander E, et al. Human papillomavirus infection is transient in young women: a population-based cohort study. J Infect Dis 1995;171:102630.[Medline]
26 Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis 1996;174:67989.[Medline]
27 Jacobs MV, Roda Husman AM, van den Brule AJ, Snijders PJ, Meijer CJ, Walboomers JM. Group-specific differentiation between high- and low-risk human papillomavirus genotypes by general primer-mediated PCR and two cocktails of oligonucleotide probes. J Clin Microbiol 1995;33:9015.[Abstract]
28 Ashley RL, Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera. J Clin Microbiol 1988;26:6627.[Medline]
29 Ashley RL. Type-specific antibodies to HSV-1 and -2: review of methodology. Herpes 1998;5:338.
30 Smith JS, Herrero R, Munoz N, Eluf-Neto J, Ngelangel C, Bosch FX, et al. Prevalence and risk factors for herpes simplex virus type 2 infection among middle-age women in Brazil and the Philippines. Sex Transm Dis 2001;28:18794.[Medline]
31 Wang SP, Grayston JT. Micro immunofluorescence antibody responses in Chlamydia trachomatis infection: a review. In: Mardh PA, Holmes KK, Oriel JD, editors. Chlamydial infections. Amsterdam (The Netherlands): Elsevier-Biomedical Press; 1982. p. 30116.
32 Breslow NE, Day NE. Statistical methods in cancer research. Volume I - The analysis of case-control studies. IARC Sci Publ 1980;(32):5338.[Medline]
33 Karlsson R, Jonsson M, Edlund K, Evander M, Gustavsson A, Boden E, et al. Lifetime number of partners as the only independent risk factor for human papillomavirus infection: a population-based study. Sex Transm Dis 1995;22:11927.[Medline]
34 Brinton LA. Epidemiology of cervical canceroverview. IARC Sci Publ 1992;(119):323.[Medline]
35 Jha PK, Beral V, Peto J, Hack S, Hermon C, Deacon J, et al. Antibodies to human papillomavirus and to other genital infectious agents and invasive cervical cancer risk. Lancet 1993;341:11168.[Medline]
36 Dillner J, Lenner P, Lehtinen M, Eklund C, Heino P, Wiklund F, et al. A population-based seroepidemiological study of cervical cancer. Cancer Res 1994;54:13441.[Abstract]
37 Daling JR, Madeleine MM, McKnight B, Carter JJ, Wipf GC, Ashley RL, et al. The relationship of human papillomavirus-related cervical tumors to cigarette smoking, oral contraceptive use, and prior herpes simplex virus type 2 infection. Cancer Epidemiol Biomarkers Prev 1996;5:5418.[Abstract]
38 Dillner J. Antibody responses to defined HPV epitopes in cervical neoplasia. Papillomavirus Rep 1994;5:3541.
39 Hildesheim A, Mann V, Brinton LA, Szklo M, Reeves WC, Rawls WE. Herpes simplex virus type 2: a possible interaction with human papillomavirus types 16/18 in the development of invasive cervical cancer. Int J Cancer 1991;49:33540.[Medline]
40 Lehtinen M, Dillner J, Knekt P, Luostarinen T, Aromaa A, Kirnbauer R, et al. Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study. BMJ 1996;312:5379.
41 Cowan FM, Johnson AM, Ashley RL, Corey L, Mindel A. Antibody to herpes simplex virus type 2 as serological marker of sexual lifestyle in populations. BMJ 1994;309:13259.
42 Graham S, Rawls W, Swanson M, McCurtis J. Sex partners and herpes simplex virus type 2 in the epidemiology of cancer of the cervix. Am J Epidemiol 1982;115:72935.[Abstract]
43 Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Mardh PA, Lemon SM, Stamm WE, Piot P, et al., editors. Sexually transmitted diseases. 3rd ed. New York (NY): McGraw-Hill; 1998. p. 285312.
44 York IA, Roop C, Andrews DW, Riddell SR, Graham FL, Johnson DC. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 1994;77:52535.[Medline]
45 Paludan SR, Malmgaard L, Ellermann-Eriksen S, Bosca L, Mogensen SC. Interferon (IFN)-gamma and Herpes simplex virus/tumor necrosis factor-alpha synergistically induce nitric oxide synthase 2 in macrophages through cooperative action of nuclear factor-kappa B and IFN regulatory factor-1. Eur Cytokine Netw 2001;12:297308.[Medline]
46 Hara Y, Kimoto T, Okuno Y, Minekawa Y. Effect of herpes simplex virus on the DNA of human papillomavirus 18. J Med Virol 1997;53:412.[Medline]
47 Vonka V, Kanka J, Roth Z. Herpes simplex type 2 virus and cervical neoplasia. Adv Cancer Res 1987;48:14991.[Medline]
48 Hildesheim A, Gravitt P, Schiffman MH, Kurman RJ, Barnes W, Jones S, et al. Determinants of genital human papillomavirus infection in low-income women in Washington, D.C. Sex Transm Dis 1993;20:27985.[Medline]
49 Remmink AJ, Walboomers JM, Helmerhorst TJ, Voorhorst FJ, Rozendaal L, Risse EK, et al. The presence of persistent high-risk HPV genotypes in dysplastic cervical lesions is associated with progressive disease: natural history up to 36 months. Int J Cancer 1995;61:30611.[Medline]
50 Franco EL, Villa LL, Sobrinho JP, Prado JM, Rousseau MC, Desy M, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis 1999;180:141523.[Medline]
Manuscript received January 15, 2002; revised August 9, 2002; accepted September 13, 2002.
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