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Volume 17, Number 8–August 2011
Asymptomatic Primary Merkel Cell Polyomavirus Infection among Adults
Yanis L. Tolstov, Alycia Knauer, Jian Guo Chen, Thomas W. Kensler, Lawrence A. Kingsley,1 Patrick S. Moore,1 and Yuan Chang1 Comments to Author
Author affiliations: University of Pittsburgh, Pittsburgh, Pennsylvania, USA (Y.L. Tolstov, A. Knauer, T.W. Kensler, L.A. Kingsley, P.S. Moore, Y. Chang); Qidong Liver Cancer Institute, Jiangsu, People's Republic of China (J.G. Chen); and Johns Hopkins University, Baltimore, Maryland, USA (T.W. Kensler)
Suggested citation for this article
Merkel cell polyomavirus (MCV) is a recently discovered virus that causes 80% of Merkel cell carcinomas. We examined data for 564 gay/bisexual male participants >18 years of age in the Multicenter AIDS Cohort Study in Pittsburgh, Pennsylvania, USA, and found that 447 (79.3%) were MCV-antibody positive at initial enrollment. Of the 117 MCV-seronegative men, 31 subsequently seroconverted over a 4-year follow-up period, corresponding to a 6.6% annual conversion rate. MCV immunoglobulin G levels remained detectable up to 25 years after exposure. No signs, symptoms, or routine diagnostic test results were associated with MCV infection, and no correlation between HIV infection or AIDS progression and MCV infection was noted. An initial correlation between chronic hepatitis B virus infection and MCV prevalence could not be confirmed among MCV seroconverters or in studies of a second hepatitis B virus–hyperendemic cohort from Qidong, China. In adults, MCV is typically an asymptomatic, common, and commensal viral infection that initiates rare cancers after virus (rather than host cell) mutations.
Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer most commonly occurring among the elderly and among immunosuppressed persons, including AIDS patients (1–3). By using digital transcriptome subtraction, Feng et al. recently discovered Merkel cell polyomavirus (MCV) clonally integrated in the tumor cell genome of ≈80% of MCC (4). This association between MCV and MCC has subsequently been confirmed by other investigators (5–8). MCV in MCC tumors possesses specific mutations that disable virus replication (9), which indicates that MCV is not a passenger virus and provides an explanation for how a common infection can lead to a rare tumor. MCV T antigen is specifically expressed in MCV-positive MCC tumor cells (10). T-antigen knockdown studies show that MCV T antigen is needed for the tumor phenotype in MCV-positive tumor cells (11), and the extent of tumors in the patient is correlated with levels of antibodies to MCV T antigen (12), leaving little doubt that MCV is the infectious cause for most but not all MCC tumors.
Serologic studies have been the primary tool to investigate the prevalence of various polyomaviruses in human populations (13–16). BK virus (BKV) and John Cunningham virus (JCV), for example, are ubiquitous human polyomavirus infections. Seroconversion for both occurs largely in childhood, with BKV seroprevalence reaching 75% among children >9 years of age and JCV seroprevalence estimated at >23% among those >10 years of age (17). The seroprevalence of Washington University and Karolinska Institute polyomaviruses plateau at 56% and 54%, respectively, for children 5–9 years of age (17). Longitudinal studies measuring immunoglobulin (Ig) G to BKV show stable levels throughout life with a slight tendency to decline after age 40–50 years, while JCV seropositivity tends to increase slowly from childhood into late adulthood (13,14,17,18). A serologic study of adult commercial blood donors that used human polyomavirus 6 and 7 virus-like particles showed that these viruses are also widely established in the human population with 69% and 35% seroprevalence, respectively (19).
Despite numerous reports describing seroprevalence for human polyomaviruses, less is known about seroconversion or signs and symptoms of primary polyomavirus infection (13,14,20). Two studies have reported JCV and BKV seroconversion among adults (13,20), but no data were presented describing signs or symptoms associated with infection. Bohl et al. demonstrated that antibody titers among kidney transplant donors reflect the activity and transmissibility of BKV infection (21,22). Randhawa et al. reported an inverse correlation between serum anti-BKV IgG optical density (OD) and peak urine viral load in kidney transplant recipients, suggesting a possible protective role of serum antibodies, which may impact the clinical outcome of postransplant BKV infection (20). These reports demonstrate that measurements of antiviral adaptive immune responses may provide prognostic value and reflect the clinical course of polyomavirus infection.
Serologic surveys have examined MCV prevalence in various groups, including children (16,17,23), blood donors (16,24), MCC patients (15,16,24), and the general population (15), demonstrating that MCV infection is widespread among healthy adults. Further supporting widespread infection, Chen et al. recently reported evidence for high rates of MCV seroconversion among children 3–13 years of age (23). Significantly elevated anti-MCV capsid IgG levels are present in blood from MCC patients compared with healthy controls, suggesting the possibility of resurgent MCV replication among patients before MCC development (15,16). Antibodies against MCV large T and small T antigens are less sensitive for detecting exposure to this virus but may be useful in monitoring tumor progression among some virus-positive MCC patients (12).
To examine signs, symptoms, and diagnostic test results associated with primary MCV infection, we examined participants of the Pittsburgh Men's Study, a component of the Multicenter AIDS Cohort Study (MACS). MACS recruited gay and bisexual men in 1984 and followed up at ≈6-month intervals with extensive symptom histories and physical examinations.
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Suggested Citation for this Article
Tolstov YL, Knauer A, Chen JC, Kensler TW, Kingsley LA, Moore PS, et al. Asymptomatic primary Merkel cell polyomavirus infection among adults. Emerg Infect Dis [serial on the Internet]. 2011 Aug [date cited]. http://www.cdc.gov/EID/content/17/8/110079.htm
1These authors contributed equally to this article.
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Yuan Chang, Cancer Virology Program, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213, USA; email: firstname.lastname@example.org