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Re: Lack of Serologic Evidence for Prevalent Simian Virus 40 Infection in Humans
Affiliations of authors: Department of Experimental and Diagnostic Medicine and Center of Biotechnology (GBB, AC), Center of Biotechnology and Department of Morphology and Embryology (FM, MT), University of Ferrara, Ferrara, Italy; Department of Clinical and Biological Sciences(RSA), University of Insubria, Varese, Italy.
Correspondence to: Mauro Tognon, PhD, Department of Morphology and Embryology, Chair of Applied Biology, School of Medicine, University of Ferrara, Via Fossato di Mortara 64/B, 44100 Ferrara, Italy (e-mail: tgm{at}unife.it)
We read with interest the recent article by Carter et al. (1), in which human sera were screened for antibodies to simian virus 40 (SV40). Sera were screened for SV40 antibodies by an enzyme-linked immunosorbent assay using SV40 VP1 virus-like particles (VLPs) as antigens. Although the fraction of SV40-positive human sera (6.6%) in the Carter et al. study (1) is in agreement with the results obtained in other investigations (2–6), Carter et al. report that SV40 reactivity in human sera disappeared after serum preadsorption with VLPs of BK virus (BKV) and JC virus (JCV), two ubiquitous human polyomaviruses that are related to SV40. As a consequence, Carter et al. concluded that the SV40 antibodies detected in human sera were not authentic SV40 antibodies but were BKV and/or JCV antibodies that cross-react with SV40.
The article by Carter et al. (1) deserves some comments. First, due to the sequence homology of the VP1 structural proteins (i.e., more than 80% identical) of the three polyomaviruses, BKV, JCV, and SV40, it is not surprising that the vast majority of the human antibody repertoire against the VP1 protein of the three polyomaviruses can largely overlap. This cross-reactivity, in turn, increases the probability that immunodominant epitopes are represented within the family of VP1 antigenic determinants common to all three polyomaviruses. Coexistence of immunodominance and cross-reactivity has been largely documented in the literature (7). Thus, both qualitative and quantitative differences in the antibody response to the epitopes present only in the SV40 VP1 structural protein may be difficult to determine, particularly if an assay based on serum preadsorption with BKV and JCV VLPs is used as the sole means of detection.
Second, there is variability in the antibody response to SV40 among individuals. For example, in a study (6) of human sera from children under 5 years of age in Morocco who were affected by poliomyelitis, 100% of the serum samples contained antibodies to SV40. However, in the same study, human sera from SV40-unaffected individuals in Morocco, Zaire, Sierra Leone, and Poland contained antibodies to SV40 in only 0.4%–5.3% of the samples, a percentage that is comparable to the results of other studies (1–5). This observation suggests that, under particular circumstances, humans can display a strong and specific antibody response to SV40.
Third, because of the ubiquity of the two human polyomaviruses, BKV and JCV, and because of the antigenic cross-reactivity in the structural proteins of the three polyomaviruses, BKV, JCV, and SV40, it is very difficult to find human sera that are positive for antibodies to SV40 and negative for antibodies to BKV and JCV. However, a human serum sample with antibodies only to SV40 has been detected in one study (6), suggesting that specific SV40 antibodies can be produced by humans.
Fourth, although seroconversion to BKV and JCV is age dependent (5), there is no detectable age-dependent seroconversion to SV40 (1,5,6), suggesting that most of the SV40 antibodies detected in human sera are not generated by infection with BKV or JCV.
Fifth, in human sera from two immunosuppressed renal transplant patients that were examined sequentially for antibodies to BKV, JCV, and SV40 over a period of 82 and 51 weeks, respectively, a substantial rise in SV40 antibody titers was detected after the kidney transplant (6), suggesting that a latent SV40 infection, similar to a latent BKV and JCV infection, can be reactivated in humans by immunosuppression. Moreover, during the follow-up, the curve of antibody titers to SV40 was different from that of antibody titers to either BKV or JCV (6), suggesting a specific immunologic response to SV40 in these two patients.
In conclusion, although antibody cross-reaction can occur during the immunologic response of humans to polyomavirus infection, unique SV40-specific antibodies can be detected in human sera. SV40-specific antigens, such as peptides that include SV40 structural epitopes that do not cross-react with BKV and JCV capsid antigens, should be used to detect the antibody-specific response to SV40 infection in the human population.
REFERENCES
1 Carter JJ, Madeleine MM, Wipf GC, Garcea RL, Pipkin PA, Minor PD, et al. Lack of serologic evidence for prevalent simian virus 40 infection in humans. J Natl Cancer Inst 2003;95:1522–30.
2 Shah KV, Ozer HL, Pond HS, Palma LD, Murphy GP. SV40 neutralizing antibodies in sera of US residents without history of polio immunization. Nature 1971;231:448–9.[CrossRef][Medline]
3 Jafar S, Rodriguez-Barradas M, Graham DY, Butel JS. Serological evidence of SV40 infections in HIV-infected and HIV-negative adults. J Med Virol 1998;54:276–84.[CrossRef][Web of Science][Medline]
4 De Sanjose S, Shah KV, Domingo-Domenech E, Engels EA, Fernandez de Sevilla AF, Alvaro T, et al. Lack of serological evidence for an association between simian virus 40 and lymphoma. Int J Cancer 2003;104:522–4.[CrossRef][Web of Science][Medline]
5 Knowles WA, Pipkin P, Andrews N, Vyse A, Minor P, Brown DW, et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 2003;71:115–23.[CrossRef][Web of Science][Medline]
6 Minor P, Pipkin P, Jarzebek Z, Knowles WA. Studies of neutralising antibodies to SV40 in human sera. J Med Virol 2003;70:490–5.[CrossRef][Medline]
7 Berzofsky JA, Berkover IJ. Immunogenicity and antigen structure. In: Paul WE, editor. Fundamental immunology, 4th edition. Philadelphia (PA): Lippincott Raven; 1999. p. 651–99.
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J Natl Cancer Inst 2004 96: 804-805.
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