Quantitation of Human Seroresponsiveness to Merkel Cell Polyomavirus

Abstract

Merkel cell carcinoma (MCC) is a relatively uncommon but highly lethal form of skin cancer. A majority of MCC tumors carry DNA sequences derived from a newly identified virus called Merkel cell polyomavirus (MCV or MCPyV), a candidate etiologic agent underlying the development of MCC. To further investigate the role of MCV infection in the development of MCC, we developed a reporter vector-based neutralization assay to quantitate MCV-specific serum antibody responses in human subjects. Our results showed that 21 MCC patients whose tumors harbored MCV DNA all displayed vigorous MCV-specific antibody responses. Although 88% (42/48) of adult subjects without MCC were MCV seropositive, the geometric mean titer of the control group was 59-fold lower than the MCC patient group (p<0.0001). Only 4% (2/48) of control subjects displayed neutralizing titers greater than the mean titer of the MCV-positive MCC patient population. MCC tumors were found not to express detectable amounts of MCV VP1 capsid protein, suggesting that the strong humoral responses observed in MCC patients were primed by an unusually immunogenic MCV infection, and not by viral antigen expressed by the MCC tumor itself. The occurrence of highly immunogenic MCV infection in MCC patients is unlikely to reflect a failure to control polyomavirus infections in general, as seroreactivity to BK polyomavirus was similar among MCC patients and control subjects. The results support the concept that MCV infection is a causative factor in the development of most cases of MCC. Although MCC tumorigenesis can evidently proceed in the face of effective MCV-specific antibody responses, a small pilot animal immunization study revealed that a candidate vaccine based on MCV virus-like particles (VLPs) elicits antibody responses that robustly neutralize MCV reporter vectors in vitro. This suggests that a VLP-based vaccine could be effective for preventing the initial establishment of MCV infection.

Human Merkel cell polyomavirus: virological background and clinical implications

“…Seroprevalence of 50-95% is reported in adults (7,(12)(13)(14)(25)(26)(27)(28)(29). The age-specific seroprevalence of MCPyV (Fig.…”

“…When expressed in mammalian or insect cells, VP1 proteins (or VP1 + VP2 proteins) self-assemble into 45-55 nm diameter virus-like particles (VLPs) (Fig. 2) that are used in serological assays (7,(12)(13)(14).…”

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…While MCPyV infection is almost ubiquitous, MCC patients have significantly higher capsid protein antibody titers and higher MCPyV DNA levels on their skin than healthy controls, suggesting that these individuals have reduced viral control [15,18,40]. Humoral recognition of MCPyV T antigen oncoproteins on the other hand is restricted to MCC patients.…”

“…Seropositivity against the viral capsid protein VP1 as well as viral DNA from cutaneous swabs indicate that 40-88% of healthy adults have been infected, with primary exposure often occurring during childhood [13,[15][16][17][18]. Viral DNA has also been detected in the respiratory tract, saliva, urine and the gastrointestinal system, suggesting possible fecal-oral transmission [14].…”

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

“…[5][6][7] Merkel cell polyomavirus has a high seroprevalence in the general population and asymptomatic infection begins in childhood. [8][9][10][11] As one of the steps in the proposed mechanism for Merkel cell carcinoma oncogenesis, polyomavirus must integrate into the human genome. 12 Viral integration sites occur throughout the human genome without apparent specificity.…”