Merkel cell polyomavirus and associated Merkel cell carcinoma

Abstract

Merkel cell polyomavirus (MCPyV) is a ubiquitous skin infection that can cause Merkel cell carcinoma (MCC), a highly lethal form of skin cancer with a nearly 50% mortality rate. Since the discovery of MCPyV in 2008, great advances have been made to improve our understanding of how the viral encoded oncoproteins contribute to MCC oncogenesis. However, our knowledge of the MCPyV infectious life cycle and its oncogenic mechanisms are still incomplete. The incidence of MCC has tripled over the past two decades, but effective treatments are lacking. Only recently have there been major victories in combatting metastatic MCC with the application of PD-1 immune checkpoint blockade. Still, these immune-based therapies are not ideal for patients with a medical need to maintain systemic immune suppression. As such, a better understanding of MCPyV's oncogenic mechanisms is needed in order to develop more effective and targeted therapies against virus-associated MCC. In this review, we discuss current areas of interest for MCPyV and MCC research and the progress made in elucidating both the natural host of MCPyV infection and the cell of origin for MCC. We also highlight the remaining gaps in our knowledge on the transcriptional regulation of MCPyV, which may be key to understanding and targeting viral oncogenesis for developing future therapies.

Merkel Cell Polyomavirus (MCPyV) and Cancers: Emergency Bell or False Alarm?

“…NCRR is located in-between the other two and does not encode any functional protein or RNA. It possesses an essential role in the viral life cycle regulation, since it contains both the viral origin of replication (Ori) and, also, various transcription promoters [ 20 , 21 ]. Immediately upon viral infection, the expression of the early region is initiated, encoding multiple, alternatively spliced RNA transcripts, leading to distinctive gene products that are generally involved in the replication of the viral genome [ 17 ].…”

“…Immediately upon viral infection, the expression of the early region is initiated, encoding multiple, alternatively spliced RNA transcripts, leading to distinctive gene products that are generally involved in the replication of the viral genome [ 17 ]. Those are the large tumor antigen (LT), the small tumor antigen (sT), as well as a 57 kT antigens, along with the alternate LT ORF (ALTO) product [ 20 , 21 ]. The LT, sT and 57 kT antigens all share an identical sequence of 78 amino acids at their N-terminal [ 22 ].…”

“…Lastly, the viral genome also contains a gene, located on the late strand of the T antigen genes, with an opposite transcription orientation to the T antigens. The transcriptional product of this gene is a non-coding miRNA [ 20 , 21 ]. The most important viral antigens proven to play a vital part in the lytic infection are the MCPyV LT and sT antigens [ 23 ].…”

“…Regarding the sT protein, it shares the LT N-terminal region, but has a unique C-region made of a protein phosphatase 2A (PP2A) binding site [ 22 , 24 ]. Following the expression of the early-coding locus and the replication of the viral DNA, the late region is transcriptionally activated to produce the structural components of the viral capsid, major capsid protein viral protein 1 (VP1) and the minor capsid protein 2 and 3 (VP2 and VP3) [ 20 ]. The presence of VP1 and VP2 is crucial for the viral entry into the cell, whereas VP3 cannot be detected in MCPyV-infected cells or in MCPyV virions, indicating a possible conditional expression pattern [ 18 ].…”

“…Consequently, there is much to be elucidated with respect to MCPyV host potential reservoir cells and the complete MCPyV infectious cycle during infection. Despite the limitation regarding the target-cell preferences, MCPyV is not solely detectable within the skin, but also in respiratory samples, urine, and blood [ 20 , 36 ], as well as in samples extracted from numerous non-malignant tissues (e.g., spleen, bone marrow, stomach, heart), although with a comparatively low viral load [ 37 ]. Lastly, the route of MCPyV transmission has yet to be established, but suggested routes include primarily direct contact with the skin or saliva, and recently proposed ones, i.e., airborne and fecal–oral [ 18 , 29 ].…”