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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 1448-1452, June 2005
© 2005 American Association for Cancer Research

Markers of Past Infection with Simian Virus 40 (SV40) and Risk of Incident Non-Hodgkin Lymphoma in a Maryland Cohort

Dana E. Rollison1,2, Kathy J. Helzlsouer2, Neal A. Halsey3, Keerti V. Shah4 and Raphael P. Viscidi5

1 Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida and Departments of 2 Epidemiology, 3 International Health, 4 Molecular Microbiology and Immunology, and 5 Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland

Requests for reprints: Dana E. Rollison, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-745-6530; Fax: 813-632-1334. E-mail: rollisde{at}moffitt.usf.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Simian virus 40 (SV40) genome sequences have been detected in human non-Hodgkin lymphoma (NHL) tissues, and past infection with SV40 may be a risk factor for NHL. We conducted a population-based nested case-control study to investigate the association between serum antibodies to SV40 and incident NHL. Two research serum banks were established in Washington County, MD, with >45,000 volunteers contributing blood samples collected in 1974 and 1989. Incident cases of NHL diagnosed through 2002 (n = 170) were identified among participants by linkage to population-based cancer registries. Two controls were matched to each case (n = 340) on age, sex, and date of blood draw. Circulating immunoglobulin G antibodies to SV40 were measured using virus-like particle (VLP) ELISA. Positive samples were tested for cross-reactivity with JC virus (JCV) and BK virus (BKV) through competitive inhibition assays. Associations between SV40 antibody seropositivity and NHL were estimated using conditional logistic regression. Whereas SV40 antibodies were detected by VLP ELISA in 15% of cases and 10% of controls [matched odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.03-3.76], the SV40 reactivity of 85% of the SV40 antibody-positive sera was decreased by adsorption with BKV and/or JCV VLPs. Antibodies specific for SV40 (not cross-reactive) were identified in only 1.8% of cases and 1.6% of controls (OR, 1.51; 95% CI, 0.41-5.52). Our findings suggest that past infection with SV40 is not associated with an increased risk of developing NHL.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The incidence of non-Hodgkin lymphoma (NHL) has nearly doubled in the United States since the early 1970s (1). Viral infections have been considered as potential risk factors for NHL (2-4), including infection with Simian virus 40 (SV40) (5). SV40 is a natural polyomavirus infection of the rhesus macaque. Millions of Americans were potentially exposed to SV40 through accidentally contaminated polio vaccines distributed in the United States between 1955 and 1963, after which time, polio vaccines were free of SV40 (6). Levels of SV40 contamination varied across polio vaccine lots, and it is unclear how many individuals were actually exposed and infected with SV40. SV40 has been shown to be oncogenic in several laboratory models (7) and can produce B-cell lymphomas in Syrian golden hamsters (8). The T antigen, a protein coded by the virus, complexes with and subsequently inactivates tumor suppressor proteins p53 and pRb.

The evidence linking SV40 infection to NHL is inconsistent. Among nine case series which investigated SV40 in tumor tissues, six reported the presence of SV40 sequences in 10% to 43% of cases (9-14), but three failed to detect SV40 sequences from NHL tissues (15-17). Findings from two cohort studies were negative: no increases in NHL incidence rates were observed among HIV-positive individuals in the United States born in years during which the polio vaccine was contaminated with SV40 compared with individuals born later (18) or in a study of national incidence rates of NHL in Denmark (19). A population-based case-control study of NHL in San Francisco found no associations with self-reported history of polio vaccination, regardless of the year of vaccination or age at vaccination (20). A hospital-based case-control study conducted among U.S. Army Veterans observed no associations between past exposure to SV40-contaminated adenovirus vaccine and NHL, brain tumors, or mesothelioma (21). None of these four studies incorporated biomarkers of SV40 exposure. A hospital-based case-control study of NHL in Spain observed an inverse association between B-cell lymphomas and the presence of serum antibodies to SV40 (5.9% positive in cases versus 9.5% controls; ref. 22). The inactivated polio vaccine was not used universally in Spain (22); thus, the magnitude of opportunity for SV40 exposure in this study population is unclear. A recent population-based case-control study in the United States observed no increased risk of NHL associated with serum antibodies to SV40 measured after NHL diagnosis (23).

To investigate the association between past SV40 infection and the subsequent risk of NHL, we conducted a population-based case-control study of serum antibodies to SV40 and incident NHL, nested within two community-based cohort studies in Washington County, MD.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
A research serum bank was established in Washington County, MD, with 23,951 specimens collected from county residents in August through November, 1974. This campaign was entitled "CLUE" for the slogan, "Give us a clue to heart disease and cancer." A second CLUE campaign was conducted between May and November 1989 with the collection of 25,079 blood specimens from county residents. Participants completed a brief baseline questionnaire at the time of blood donation. Serum (1974) and plasma (1989) from participants were stored at –70°C to –73°C. All participants consented to the use of their stored blood in future research studies. The protocol for the current study was approved by the Committee on Human Research, the institutional review board at the Johns Hopkins Bloomberg School of Public Health.

Cases of NHL occurring among CLUE cohort members through 2002 were identified by linkage to the Washington County Registry [International Classification of Diseases, Ninth Revision (ICD-9) code 200 or 202], which has been maintained since 1958, linkage to the Maryland State Cancer Registry since 1992, and periodic review of death certificates. Cases were defined as participants of CLUE I, CLUE II, or both, who were county residents at the times of both blood donation and subsequent diagnosis with NHL, where NHL was their first cancer diagnosis with the possible exceptions of nonmelanoma skin cancer or cervical cancer in situ. NHL subtypes were classified using ICD-9/ICD-10 morphology codes: diffuse large B-cell lymphomas (ICD 9680/3, 9682/3, 9684/3, and 9680), follicular B-cell lymphomas (ICD 9675/3, 9690/3, 9691/3, 9695/3, 9696/3, 9698/3, and 9690), T-cell lymphomas (ICD 9700/3), others/not specified (ICD 9590/3, 9591/3, 9592/3, 9593/3, 9595/3, 9670/3, 9672/3, 9673/3, 9686/3, 9687/3, 9694/3, 9699/3, 9711/3, 9823/3, 9940/3, 9533/1, 9693/3, and 9685/3). Cases (n = 172) were identified. Two cases were excluded due to inadequate amounts of available serum.

Two controls were matched to each case on sex, race, age within 1 year, date of blood draw within 2 weeks, freeze/thaw status of the serum, and participation in CLUE I, CLUE II, or both. Controls were residents of Washington County at the time of blood donation and not known to have died or developed cancer (except for possibly nonmelanoma skin cancer or cervical cancer in situ) as of the date of diagnosis of the case. Matching criteria were relaxed in certain cases to achieve a match: seven controls were up to 2 years older than their matched cases, and for four case-control pairs, date of blood draw differed as much as 1 month. Participants in this study include 74 NHL cases and 120 controls selected for a previous case-control study of pesticide exposure conducted within these cohorts in 1994 (24).

Laboratory Methods
Virus-like particles (VLP) were purified from insect cells infected with recombinant baculoviruses expressing the VP1 major capsid protein of SV40, as previously described (25). For ELISA, PolySorp microtiter plates (Nunc, Naperville, IL) were sensitized with 20 to 30 ng of VLP protein per well. The serum dilution (1:400) was left to react for 1 hour at 37°C. Antigen-bound immunoglobulin was detected with peroxidase-conjugated antibodies against human immunoglobulin G (Zymed, San Francisco, CA). After 30 minutes at room temperature, color development was initiated by the addition of 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulfonate) hydrogen peroxide solution. The reaction was stopped after 20 minutes, and absorbance (A) was measured at 405 nm. Absorbance values of >0.1 were considered positive by ELISA based on previous results (25). The sensitivity and specificity of the ELISA for SV40 detection in humans is unknown because there are no human reference standards, but the assay demonstrates 100% sensitivity and 100% specificity for SV40 infection in macaques (25).

Previous studies have shown that there is serologic cross-reactivity between SV40 and the two related human polyomaviruses, JC virus (JCV) and BK virus (BKV) (25, 26). Therefore, samples testing positive for SV40 by ELISA underwent competitive inhibition ("blocking") assays to assess serologic cross-reactivity with JCV and BKV. VLP proteins for JCV and BKV were prepared as described above for SV40. Study serum samples were diluted 1:400 in buffer containing 4 µg/mL of SV40, BKV, or JCV VLP protein or in buffer alone. In preliminary experiments, this concentration of SV40 VLP protein in the diluent was shown to result in near maximal inhibition of SV40 antibody-positive macaque sera. After incubation of serum samples for 1 hour at 37°C on SV40-coated microtiter plates, the ELISA assay was completed as described above. The percent inhibition of SV40 reactivity by each VLP was calculated as 1 – Acompeting VLP / Abuffer control x 100. If ≥50% of the SV40 reactivity was blocked by JCV and/or BKV, then the SV40 antibodies were considered cross-reactive. "SV40-specific" reactivity was defined as SV40 reactivity that was competitively inhibited ≥50% by SV40 and <50% by both JCV and BKV (23).

Quality Control
Each case and its two matched controls were maintained in their matched set to ensure simultaneous processing. Laboratory personnel were masked as to the case-control status of each sample. Seven pooled sera samples and eight pooled plasma samples were masked and placed across matched sets to test interset reliability of the ELISA assay. Similarly, nine duplicate pairs of sera and eight duplicate pairs of plasma were placed within matched sets to assess intraset reliability, each pair drawn from a cohort member not included in the study. Across sets, seven of seven pooled sera samples were consistently negative for SV40 antibodies based on the absorbance value cut point of 0.1, whereas eight of eight pooled plasma samples were consistently positive. Among the 17 duplicate pairs of sera or plasma, all but two samples were negative for SV40 antibodies, and the two samples that tested positive were from the same duplicate pair. In addition, seven aliquots of SV40 antibody-positive monkey sera served as masked positive controls; all of them showed high absorbance values of >1.0 (mean absorbance value = 1.72, SD = 0.33).

Statistical Methods
Baseline characteristics were compared between cases and controls using {chi}2 tests. SV40 antibody status in relation to NHL was assessed in two ways. First, individuals were defined as positive or negative for SV40 antibodies based solely on the ELISA absorbance cutoff value of 0.1. To investigate a dose-response relationship, three levels of positive absorbance values were defined, based on dividing the distribution in the controls into thirds. To account for possible immunologic cross-reactivity on the ELISA, a second analysis included results from the blocking assays, where SV40 antibody-positive samples from the ELISA assay were determined to be SV40-specific or cross-reactive, as described above. In both analyses, the association between SV40 antibody seropositivity and NHL was estimated by calculating matched odds ratios (OR) and 95% confidence intervals (95% CI) using conditional logistic regression. ORs were similar using either serum samples collected in 1974 or plasma samples collected in 1989; thus, all were combined. Forty-seven of the 170 cases and their matched controls donated blood to both CLUE I in 1974 and CLUE II in 1989; the variance of the repeated measures of SV40 antibody levels in this subgroup was incorporated into logistic regression models using a robust sandwich estimation method (27).

Education, smoking, and body mass index were considered as potential confounders. When these factors were placed individually into regression models with SV40 antibody serologic status, no appreciable changes in ORs for SV40 antibodies and NHL were observed; thus, these factors were not included in the final regression models. Analyses were stratified by NHL subtype, combining diffuse large B-cell lymphoma with follicular B-cell lymphoma, after initial analyses revealed homogenous risk estimates for these subtypes. One case of T-cell lymphoma was identified and combined with the other/unknown group. Analyses were also stratified by two categories of time between blood draw and diagnosis (<11 and ≥11 years), defined by the median value in the cases. All statistical tests were two sided. Analyses were conducted using SAS, version 8 (SAS Institute, Inc., Cary, NC).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline characteristics are presented for NHL cases and matched controls in Table 1. All but one case was White, and there were more females than males, reflecting the race and sex distributions in the underlying CLUE cohorts. No statistically significant differences between cases and controls were observed for education, smoking status, or body mass index (Table 1).


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  		Table 1. Baseline characteristics of NHL cases and matched controls: Washington County, MD (1975-2002)

 
SV40 antibody levels in the human sera were low; the median absorbance value of the SV40-positive human sera was 0.23 compared with 1.86 for the macaque sera. Based on the dichotomous absorbance cut point of 0.1, SV40 antibodies were detected using the ELISA assay in 15% of cases and 10% of controls (matched OR, 1.97; 95% CI, 1.03-3.76; Table 2). This association was particularly strong for B-cell lymphomas (OR, 2.85; 95% CI, 1.32-6.17), whereas SV40 antibodies were not associated with lymphomas of other/unknown subtypes (OR, 0.92; 95% CI, 0.30-2.83). There was no dose-response relationship between SV40 antibody levels and overall risk of NHL (Table 2).


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  		Table 2. SV40 antibody seroprevalence and risk of incident NHL: Washington County, MD (1975-2003)

 
Of the 33 cases and 41 controls who tested positive by ELISA, 27 (82%) case samples and 31 (76%) control samples exhibited cross-reactivity with JCV and/or BKV on the blocking assays (Table 2). Two case samples and three control samples contained antibodies that were not specific to JCV, BKV, or SV40. Only four case samples and seven control samples contained SV40-specific antibodies (i.e., antibodies reacted with SV40 and did not react with JCV or BKV; Table 2). Whereas the cross-reactive antibodies were positively associated with NHL (OR, 2.07; 95% CI, 1.03-4.16), there was no statistically significant difference between the proportion of cases and controls with antibodies specific to SV40 (OR, 1.51; 95% CI, 0.41-5.52; Table 2). The magnitude of the observed associations was slightly greater when considering only B-cell NHL, although the general pattern of risk was similar (Table 2).

The median time between blood draw and NHL diagnosis was 10.8 years (SD = 7.7 years). Results were similar for cases diagnosed 11 years before or 11 years after the time of blood draw (Table 3). Only one case diagnosed within 11 years of blood draw and three cases diagnosed ≥11 years after blood draw had SV40-specific antibodies, and no statistically significantly associations were observed with NHL for either of these groups (Table 3). Sixteen cases were diagnosed within 2 years of blood draw, none of which were positive for SV40-specific antibodies, and exclusion of these cases did not appreciably change the results (data not shown). Similar results by time to diagnosis were obtained when cases of other/unknown subtypes were excluded (data not shown).


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  		Table 3. SV40 antibody seroprevalence and risk of incident NHL by time from blood draw to diagnosis: Washington County, MD (1975-2003)

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Individuals positive for SV40 antibodies based on the ELISA assay alone had an increased risk for developing NHL, particularly B-cell NHL (OR, 2.85; 95% CI, 1.32-6.17), but further investigation showed that the association was due to cross-reactivity with JCV and/or BKV. Presence of antibodies specific to SV40, as measured from serum collected years before diagnosis, was not associated with the subsequent development of NHL.

This is the first prospective study of SV40 antibodies and the development of NHL. In contrast to analyses of NHL incidence rates by birth cohorts, the measurement of antibodies as biomarkers of past SV40 infection provides exposure data at the individual level. However, antibodies themselves are limited in their specificity for SV40 infection status. If individuals were exposed to inactivated SV40 through the polio vaccine, they could have produced antibodies to SV40 capsid proteins in the absence of active infection. In this case, these individuals would be misclassified as having past SV40 infection. Measurement of antibodies to the T antigen might clarify this issue, because only those with active infection could develop T antibodies. However, only 4 of 217 NHL case samples and 7 of 434 control samples had antibodies specific to SV40 in this study. Therefore, it is unlikely that a true association between SV40 infection and NHL is masked by nondifferential misclassification of exposed, noninfected individuals as infected in this small subset. The small number of participants who had SV40-specific antibodies limited the interpretation of results stratified by NHL subtype.

SV40 antibodies were measured in this study using VLP-based ELISA assays, which were previously validated against the plaque neutralization assay for detection of SV40 antibodies in SV40-infected macaque sera (25). Recent data suggest that the low level of SV40-neutralizing antibodies detected in human sera are largely the result of cross-reactivity with BKV and JCV antibodies (28). Therefore, we used competitive inhibition or "blocking" assays to determine the specificity of SV40 antibodies initially detected by ELISA, an approach used also by other investigators (23, 26). Consistent with previous studies, SV40 antibodies detected by ELISA in the present study were highly cross-reactive with JCV and BKV VLPs, and the actual prevalence of SV40-specific antibodies was low (2%).

Whereas the effect of long-term storage on SV40 antibodies in human sera has not been documented, there is no reason to suspect freezing would differentially affect antibodies to SV40 versus antibodies to JCV and BKV, which were highly prevalent among study samples. No significant differences in SV40 antibody levels were observed between samples collected in 1974 and 1989. Finally, even if freezing had a small effect on antibody levels, no bias would be introduced into the results, because cases and controls were matched on the number of freeze/thaw cycles of the sera.

All study participants were born before 1960; thus, all were potentially exposed to SV40-contaminated polio vaccine. By 1961, an estimated 62% of individuals under the age of 60 received polio vaccine, with 88% coverage among those 20 years old and younger (29). In the present study, no significant differences were observed in SV40 antibody seropositivity between those who were younger or older than age 20 in 1961 (data not shown). Human transmission of SV40 has been proposed as another route of exposure for individuals born after 1963 (30). However, if SV40 infection is truly associated with NHL, then SV40 antibody levels should be higher among NHL cases than controls in a case-control study, regardless of the route of SV40 infection.

Cohort participants who moved out of Maryland would have been lost to follow-up, as incident cases were ascertained only within the state. However, the population of Washington County is increasing, and NHL is a relatively rare cancer; thus, few cases are likely to have been missed. Additionally, those who moved out of state had the same opportunity for SV40 exposure than those who remained in the state, because all were potentially vaccinated for polio. Limited information was available for other suspected risk factors for NHL at baseline, including birth order, income, and history of infections. These factors, if associated with polio vaccination, could have been negative confounders of the association between SV40 infection and NHL, assuming that polio vaccination was the main source of SV40 exposure.

Our results indicate that past SV40 infection is not associated with the development of NHL. The observed association between NHL and antibodies to SV40 that cross-react with JCV and/or BKV suggests that these polyomaviruses should be examined further as potential risk factors for NHL. Future epidemiologic studies of polyomavirus antibodies and cancer should also incorporate biomarkers of immunologic cross-reactivity with other oncogenic viruses to investigate the potential interplay between viruses in the etiology of NHL.


   Acknowledgments
 
We thank Judith Hoffman-Bolton at the George W. Comstock Center for Public Health Research and Prevention for assistance with participant selection; the Clinical Immunization Safety Assessment Network for technical and administrative support, especially Christine Casey and Philip LaRussa for reviewing a draft of the article; the laboratory assistance of Barbara Clayman (Johns Hopkins University School of Medicine, Baltimore, MD); and all who participated in the CLUE cohorts.


   Footnotes
 
Grant support: National Cancer Institute grants 5 UO1 CA086308 (Early Detection Research Network), AG18033 (Odyssey Cohort), and 2 T32 CA093-14-19 (D.E. Rollison) and Centers for Disease Control and Prevention contract 200-2002-00732.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: These data were supplied in part by the Maryland State Cancer Registry, Department of Health and Mental Hygiene, Baltimore, MD.

Conflict of interest: Dr. K.V. Shah has consulted with pharmaceutical companies that manufactured polio vaccines. No funding was provided by industry or commercial enterprises, and these parties had no role in the study design, data collection, analysis or interpretation, or writing the report.

Disclaimer: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Received 9/13/04; revised 12/ 2/04; accepted 1/20/05.


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 Introduction
 Materials and Methods
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 Discussion
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