Merkel cell polyomavirus

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Human polyomavirus 5
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Monodnaviria
Kingdom: Shotokuvirae
Phylum: Cossaviricota
Class: Papovaviricetes
Order: Sepolyvirales
Family: Polyomaviridae
Genus: Alphapolyomavirus
Species:
Human polyomavirus 5

Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008 in Pittsburgh, Pennsylvania. [1] It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called digital transcriptome subtraction. [2] MCV is one of seven currently known human oncoviruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. [3] Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. MCV appears to be a common—if not universal—infection of older children and adults. [4] [5] It is found in respiratory secretions, suggesting that it might be transmitted via a respiratory route. However, it has also been found elsewhere, such as in shedded healthy skin and gastrointestinal tract tissues, thus its precise mode of transmission remains unknown. [6] [7] In addition, recent studies suggest that this virus may latently infect the human sera [8] and peripheral blood mononuclear cells. [9]

Contents

Most MCV viruses found in MCC tumors, however, have at least two mutations that render the virus nontransmissible: 1) The virus is integrated into the host genome and 2) The viral T antigen has truncation mutations that leave the T antigen unable to initiate DNA replication needed to propagate the virus. [10]

Evidence that MCV is the cause for most MCC tumors comes from studies in which T antigen oncoproteins from the virus are inhibited. Knockdown of these viral proteins causes cells from MCV-positive MCC tumors to die whereas there is no effect on cells from tumors that are uninfected with the virus. [11] This indicates that MCV is necessary to maintain the virus-positive tumor cells. Further, clonal pattern of MCV insertions into MCC cell genomes indicates that the virus was present in the Merkel cell before it underwent cancerous transformation. The IARC has recently classified MCV as a class 2A carcinogen. [12]

Classification

Family tree of the polyomaviruses, based on large T antigen sequence Polyomavirustree.jpg
Family tree of the polyomaviruses, based on large T antigen sequence
Electron microphotograph (x50,000) of MCV capsids artificially produced as virus-like particles by expressing MCV structural proteins in cells. The 55-60 nm viral capsids have typical icosahedral symmetry found in polyomaviruses. MCV VLP EM PTA staining.jpg
Electron microphotograph (x50,000) of MCV capsids artificially produced as virus-like particles by expressing MCV structural proteins in cells. The 55–60 nm viral capsids have typical icosahedral symmetry found in polyomaviruses.
A complete MCV genome was designed from multiple Merkel Cell carcinoma tumors and normal human tissues. MCV genomes.jpg
A complete MCV genome was designed from multiple Merkel Cell carcinoma tumors and normal human tissues.

Polyomaviruses are small (~5400 base pair), non-enveloped, double-stranded DNA viruses. MCV is the fifth polyomavirus that infects humans to be discovered. It belongs to the murine polyomavirus group, one of the three main clades of polyomaviruses. [1] (The group is named for murine polyomavirus, the earliest virus of the group to be discovered, and does not imply that MCV is transmitted to humans from rodents.) Although it has been confused with the controversial SV40 virus in some blog postings, it is a distinct virus.[ citation needed ]

MCV is genetically most closely related to the African green monkey lymphotropic polyomavirus [1] (formerly known as African green monkey lymphotropic papovavirus), [14] which is consistent with MCV coevolving with human primates.

The prototype sequence of MCV has a 5387 base pair double-stranded DNA (dsDNA) genome and encodes characteristic polyomavirus genes from opposite strands including a large T antigen, a small T antigen (LT and sT, respectively, from early strand) and viral capsid proteins VP1 and VP2/3 genes (from late strand) [15] Our Viruses - MCV. MCV T antigen has similar features to the T antigens of other polyomaviruses, which are known oncoproteins, and is expressed in human tumors. [1] [10] The T antigen is a spliced gene that forms multiple different proteins depending on the splicing pattern. Both large T and small T oncoproteins are probably needed to transform healthy cells into cancer cells, and they act by targeting tumor suppressor proteins, such as retinoblastoma protein. The LT antigen possesses a helicase motif needed for virus replication that is deleted in MCC tumors. Unlike for other polyomaviruses, MCV sT antigen transforms cells in vitro [16] by activating cap-dependent translation.

MCV also expresses a microRNA (miRNA) known as MCV-miR-M1 from its late strand which bears perfect complementarity to LT and has been shown to negatively regulate LT expression . [17] In addition to its role in regulating MCV LT expression and DNA replication, MCV-miR-M1 has been shown to directly target and downregulate the expression of host cell immune related transcript SP100 [18] and its role in the establishment of long-term persistent infection has been demonstrated in vitro. [19]

Viral cause for Merkel cell carcinoma

Merkel cell carcinoma is a highly aggressive type of skin cancer that was first described by Cyril Toker in 1972 as "trabecular tumor of the skin". [20] Based on its origin, the cancer cell type is called a neuroectodermal tumor. Although rare compared with other skin cancers, the incidence of Merkel cell carcinoma in the United States tripled between 1986 and 2001, to around 1400 cases per year. [21]

Merkel cell carcinoma is mainly seen in older individuals. [21] It is known to occur at increased frequency in people with immunodeficiency, including transplant recipients and people with AIDS, [22] [23] and this association suggests the possibility that a virus or other infectious agent might be involved in causing the cancer. Kaposi's sarcoma and Burkitt's lymphoma are examples of tumors known to have a viral etiology that occur at increased frequency in immunosuppressed people. Other factors associated with the development of this cancer include exposure to ultraviolet light. [21]

Eight of 10 Merkel cell carcinoma tumors initially tested were found to be infected with MCV. [1] In these tumors, the virus has integrated into the cancer cell genome and can no longer freely replicate. Recent studies from other laboratories have reproduced these findings: in one study 30 of 39 (77%) of Merkel cell tumors were MCV positive; [24] in another study, 45 of 53 (85%) Merkel cell tumors were positive.

Sequencing of the virus from Merkel cell cancers reveals that it generally has tumor-specific mutations that truncate the MCV T antigen. These mutations (which are not found in native virus obtained from nontumor sites) eliminate the T antigen helicase, preventing the integrated virus from replicating independently from the host cancer cell. [10] The tumor is therefore a "dead-end host" for MCV. [25] Normally, the virus exists as circular episome (or plasmid) within the cell and its DNA is packaged into viral capsids and transmitted to other cells. In tumors, the viral DNA has broken and become integrated into human DNA within the tumor, so that the virus is no longer transmissible. The integrated virus cannot be excised from the host cell and it must replicate as the host cell is replicated. Examination of infected tumors reveals that the majority have a clear monoclonal pattern, indicating that the virus integrated into a single cell before it began its cancerous expansion. [1] For this reason, there is very strong evidence that MCV causes some, but not all, Merkel cell carcinomas. MCV can also be found in healthy tissues from people without Merkel cell carcinoma. A complete MCV genome (MCV-HF) was designed from multiple tumor-type MCV genomes and examined with successful replication capability in vitro. [26] The identical sequences were found in human normal skins. [27] While the precise prevalence of infection is unknown in humans, it is likely that most infections do not cause cancers. [28]

Prevention, diagnosis, and treatment

Persons who have Merkel cell carcinoma with this virus are not infectious to others and no infectious restrictions are warranted. The reasons for this are: 1) the virus in tumors is already mutated and no longer can be transmitted from tumors, and 2) most persons are already naturally exposed to this virus as children and young adults by other asymptomatic carriers.[ citation needed ]

Based on current data, prevention advice for MCC is similar to other skin cancers, such as avoiding sunburns and unnecessary sun exposure together with use of sun lotion. This may prevent mutations in the virus that increase risk for MCC among those already infected with MCV. Persons with immunosuppression (e.g., AIDS or organ transplant patients) are at higher risk for this cancer and may benefit from periodic skin examinations. Emergence of a painless lump that expands rapidly, especially among persons over age 50 or persons with immunosuppression, warrants examination by a physician. Biopsy of a Merkel cell tumor should readily provide a diagnosis and when caught early, has a good prognosis through standard treatment. At this time there are no vaccines or medications that can prevent MCV infection or prevent emergence of Merkel cell carcinoma.[ citation needed ]

Detection of the virus is still at a research phase and is generally not available as a clinical test. Detection of viral DNA is performed by PCR or by Southern blot. Caution is needed in interpreting results from PCR since it is prone to false-positive contamination and a substantial fraction of healthy skin samples may harbor low-level infection. [27] Sequencing of the viral genome may determine whether or not tumor-specific mutations are present.[ citation needed ]

Antibodies have been developed to stain for T antigen in tumor tissues [29] and appear to be specific for MCV-infected tumor cells. [30] [31] Blood tests have also been developed [4] [5] that show the majority of adults have been previously exposed to MCV and may continue to carry it as an asymptomatic infection.

Treatment guidelines do not differ for Merkel cell carcinoma infected with MCV or without MCV. A recent country-wide study from Finland suggests that MCV-positive tumors have a better prognosis than uninfected tumors [32] (although this has not been found in other studies [25] ). If this is confirmed, routine detection of the virus may provide a future benefit for medical guidance. The virus itself is not known to be susceptible to current antiviral medications.

Recent studies reveal that the survivin oncoprotein is activated by MCV large T protein targeting the cellular retinoblastoma protein [33] and that survivin inhibitors can delay tumor progression in animal models. Clinical trials are now being organized to determine whether this has any benefit in humans. The importance of this finding is that a promising rational drug target was uncovered within four years of the initial discovery of the virus and that other new treatments might be rapidly developed now that the cause of the cancer is known. MCV is a target for cell-mediated immune responses, and so important research efforts are being focused on immunologic therapies that may benefit MCC patients.[ citation needed ]

Discovery and characterization

Yuan Chang and Patrick S. Moore discovered Kaposi's sarcoma-associated herpesvirus by a physical subtraction method in 1994. [34] A virtual subtraction method was developed by Huichen Feng in the lab as a novel high-throughput sequencing technique of digital transcriptome subtraction (DTS)New Pathogen Discovery [2] to search for the presence of a virus in Merkel cell tumors. [1] In this method, all mRNAs from a tumor are converted into cDNAs and sequenced to a depth likely to sequence a viral cDNA if it is present. The sequences are then compared with the human genome and all human sequences are "subtracted" to leave a group of sequences that are most likely nonhuman. When this was performed on four cases of Merkel cell carcinoma, one cDNA was found that was similar to sequences of known polyomaviruses but clearly distinct enough that it could be shown to be a new virus. [1] Genetic sequences from nearly 400,000 mRNAs were analyzed for the study. Once the virus was found, Feng and coworkers quickly determined that infected Merkel cell carcinomas have the virus in an integrated monoclonal pattern and 80% of tissues taken from patients with MCC were positive for the virus. This was quickly confirmed by studies of MCC patients from around the world, including evidence for monoclonal integration of the virus in these tumors. [24] [25] [35] [36]

As a cause for Merkel cell carcinoma

While the original authors conservatively noted that it is "too early to tell" whether MCV is a cause of Merkel cell carcinoma, general scientific opinion now suggests that the virus causes most, but not all Merkel cell tumors. The virus is monoclonally integrated into the tumor when present, indicating that the proto-tumor cell was infected with the virus prior to its cancerous expansion. Mutations in the T antigen render the virus noninfectious, and therefore it is not a passenger virus that infected the tumor after the tumor had already started. Finally, the T antigen oncogene is expressed in all of the tumor cells and when it is inhibited ("knocked down" by RNAi), MCV-positive cells die. Thus, the virus is required for MCV-positive tumors to grow. It is likely that additional host cell mutations act in concert with the integrated virus to actually cause the tumor. Merkel cell carcinoma is associated with exposure to ultraviolet (UV) light and to ionizing radiation, and it is likely that these mutagens increase the rate of mutation in either the virus or the Merkel cell genome, contributing to the risk for cancer after infection.[ citation needed ]

The reasons why 20% of Merkel cell carcinoma are negative for the virus remain completely unknown but speculations include the possibility that "Merkel cell carcinoma" is actually two or more closely related cancers, only one of which is infected with MCV. Misdiagnosis of this difficult cancer may also account for some of the negative results. Only a very small proportion of people infected with MCV develop the cancer. At this time no test for the presence of the virus is generally available, nor would patients be advised to change their treatment based on knowledge of MCV infection status. MCC patients can be enrolled in research studies, but these are not likely to directly benefit participants. [37] Reducing risk of UV exposure through sun screens is likely to reduce the risk of Merkel cell carcinoma as well as other skin cancers.

Moore has suggested that if his findings are confirmed, information about the virus could lead to a blood test or a vaccine that could improve the management of the disease or aid in prevention, much as the human papillomavirus vaccine can be used to prevent cervical cancer. Chang explained that study of the virus may assist in understanding other human cancers. "Once the virus integrates, it could express an oncoprotein, or it could knock out a gene that suppresses tumor growth. Either way, the results are bound to be interesting." [38] [39]

Other associations

Possible associations with cervical carcinoma, cutaneous squamous cell carcinoma, Bowen's disease, basal cell skin carcinoma, extrapulmonary small cell carcinoma, and EGFR mutation-driven non-small cell lung cancer have been reported. [40] [41] [42] [43] [44] [ excessive citations ]

Related Research Articles

<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2024, there are eight recognized genera. 14 species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication and transcription.

<i>Human polyomavirus 2</i> Species of virus

Human polyomavirus 2, commonly referred to as the JC virus or John Cunningham virus, is a type of human polyomavirus. It was identified by electron microscopy in 1965 by ZuRhein and Chou, and by Silverman and Rubinstein, and later isolated in culture and named using the two initials of a patient, John Cunningham, with progressive multifocal leukoencephalopathy (PML). The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with immunosuppressive drugs.

<span class="mw-page-title-main">Oncovirus</span> Viruses that can cause cancer

An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the letters "RNA" removed, it now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus". The vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. Oncoviruses have been important not only in epidemiology, but also in investigations of cell cycle control mechanisms such as the retinoblastoma protein.

<span class="mw-page-title-main">Merkel-cell carcinoma</span> Rare and highly aggressive skin cancer

Merkel-cell carcinoma (MCC) is a rare and aggressive skin cancer occurring in about three people per million members of the population. It is also known as cutaneous APUDoma, primary neuroendocrine carcinoma of the skin, primary small cell carcinoma of the skin, and trabecular carcinoma of the skin. Factors involved in the development of MCC include the Merkel cell polyomavirus, a weakened immune system, and exposure to ultraviolet radiation. Merkel-cell carcinoma usually arises on the head, neck, and extremities, as well as in the perianal region and on the eyelid. It is more common in people over sixty years old, Caucasian people, and males. MCC is less common in children.

<span class="mw-page-title-main">Patrick S. Moore</span> Irish and American virologist and epidemiologist

Patrick S. Moore is an American virologist and epidemiologist who co-discovered together with his wife, Yuan Chang, two different human viruses causing the AIDS-related cancer Kaposi's sarcoma and the skin cancer Merkel cell carcinoma. Moore and Chang have discovered two of the seven known human viruses causing cancer. The couple met while in medical school together and were married in 1989 while they pursued fellowships at different universities.

Trichodysplasia spinulosa polyomavirus is a member virus of Human polyomavirus 8 that infects human hosts. First discovered in 2010, TSPyV is associated with Trichodysplasia spinulosa, a rare skin disease only seen in immunocompromised patients. The virus causes hyperproliferation and enlargement of hair follicles by modulating PP2A protein phosphatase signaling pathways. TSPyV was the eighth human polyomavirus to be discovered, and one of four associated with human disease, out of 13 human polyomaviruses known as of the 2015 update to polyomavirus taxonomy released by the International Committee on Taxonomy of Viruses.

<span class="mw-page-title-main">Digital transcriptome subtraction</span>

Digital transcriptome subtraction (DTS) is a bioinformatics method to detect the presence of novel pathogen transcripts through computational removal of the host sequences. DTS is the direct in silico analogue of the wet-lab approach representational difference analysis (RDA), and is made possible by unbiased high-throughput sequencing and the availability of a high-quality, annotated reference genome of the host. The method specifically examines the etiological agent of infectious diseases and is best known for discovering Merkel cell polyomavirus, the suspect causative agent in Merkel-cell carcinoma.

<span class="mw-page-title-main">Murine polyomavirus</span> Species of virus

Murine polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family. The first member of the family discovered, it was originally identified by accident in the 1950s. A component of mouse leukemia extract capable of causing tumors, particularly in the parotid gland, in newborn mice was reported by Ludwik Gross in 1953 and identified as a virus by Sarah Stewart and Bernice Eddy at the National Cancer Institute, after whom it was once called "SE polyoma". Stewart and Eddy would go on to study related polyomaviruses such as SV40 that infect primates, including humans. These discoveries were widely reported at the time and formed the early stages of understanding of oncoviruses.

Hamster polyomavirus is an unenveloped double-stranded DNA virus of the polyomavirus family whose natural host is the hamster. It was originally described in 1967 by Arnold Graffi as a cause of epithelioma in Syrian hamsters.

WU polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in samples of human respiratory secretions, originally from a child patient in Australia who presented with clinical signs of pneumonia and in whom other common respiratory viruses were not detected. Follow-up studies identified the presence of WU virus in respiratory secretion samples from patients in Australia and the United States, suggesting that, like other human polyomaviruses, WU virus is widely distributed.

KI polyomavirus is a virus of the family Polyomaviridae. It was discovered in 2007 in stored samples of human respiratory secretions collected by the Karolinska Institute, after which the virus is named.

<span class="mw-page-title-main">Agnoprotein</span> Viral protein found in some polyomaviruses

Agnoprotein is a protein expressed by some members of the polyomavirus family from a gene called the agnogene. Polyomaviruses in which it occurs include two human polyomaviruses associated with disease, BK virus and JC virus, as well as the simian polyomavirus SV40.

Human polyomavirus 7 (HPyV7) is a virus of the polyomavirus family that infects human hosts. It was discovered in 2010 and is a common component of the skin flora in healthy adults. There is limited evidence from case reports linking the virus to a skin rash occurring in immunocompromised organ transplant recipients.

Human polyomavirus 6 (HPyV6) is a virus of the polyomavirus family that infects human hosts. It was discovered in 2010 and is a component of the skin flora in healthy adults.

MW polyomavirus is a virus of the polyomavirus family that infects human hosts. It was discovered in 2012 and reported independently by several research groups. It has been identified mostly in stool samples from children and has been detected in a variety of geographic locations.

New Jersey polyomavirus is a virus of the polyomavirus family that infects human hosts. It was first identified in 2014 in a pancreatic transplant patient in New Jersey. It is the 13th and most recent human polyomavirus to be described.

<span class="mw-page-title-main">Large tumor antigen</span>

The large tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. LTag is expressed early in the infectious cycle and is essential for viral proliferation. Containing four well-conserved protein domains as well as several intrinsically disordered regions, LTag is a fairly large multifunctional protein; in most polyomaviruses, it ranges from around 600-800 amino acids in length. LTag has two primary functions, both related to replication of the viral genome: it unwinds the virus's DNA to prepare it for replication, and it interacts with proteins in the host cell to dysregulate the cell cycle so that the host's DNA replication machinery can be used to replicate the virus's genome. Some polyomavirus LTag proteins - most notably the well-studied SV40 large tumor antigen from the SV40 virus - are oncoproteins that can induce neoplastic transformation in the host cell.

<span class="mw-page-title-main">Small tumor antigen</span>

The small tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. STag is expressed early in the infectious cycle and is usually not essential for viral proliferation, though in most polyomaviruses it does improve replication efficiency. The STag protein is expressed from a gene that overlaps the large tumor antigen (LTag) such that the two proteins share an N-terminal DnaJ-like domain but have distinct C-terminal regions. STag is known to interact with host cell proteins, most notably protein phosphatase 2A (PP2A), and may activate the expression of cellular proteins associated with the cell cycle transition to S phase. In some polyomaviruses - such as the well-studied SV40, which natively infects monkeys - STag is unable to induce neoplastic transformation in the host cell on its own, but its presence may increase the transforming efficiency of LTag. In other polyomaviruses, such as Merkel cell polyomavirus, which causes Merkel cell carcinoma in humans, STag appears to be important for replication and to be an oncoprotein in its own right.

The middle tumor antigen is a protein encoded in the genomes of some polyomaviruses, which are small double-stranded DNA viruses. MTag is expressed early in the infectious cycle along with two other related proteins, the small tumor antigen and large tumor antigen. MTag occurs only in a few known polyomaviruses, while STag and LTag are universal - it was first identified in mouse polyomavirus (MPyV), the first polyomavirus discovered, and also occurs in hamster polyomavirus. In MPyV, MTag is an efficient oncoprotein that can be sufficient to induce neoplastic transformation in some cells.

References

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  5. 1 2 3 Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, Chang Y, Buck CB, Moore PS (September 2009). "Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays". International Journal of Cancer. 125 (6): 1250–6. doi:10.1002/ijc.24509. PMC   2747737 . PMID   19499548.
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  12. ↑ "Archived copy" (PDF). Archived from the original (PDF) on 2011-10-25. Retrieved 2012-07-17.{{cite web}}: CS1 maint: archived copy as title (link)
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  16. ↑ Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS (September 2011). "Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator". The Journal of Clinical Investigation. 121 (9): 3623–34. doi:10.1172/JCI46323. PMC   3163959 . PMID   21841310.
  17. ↑ Seo GJ, Chen CJ, Sullivan CS (January 2009). "Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression". Virology. 383 (2): 183–7. doi:10.1016/j.virol.2008.11.001. PMID   19046593.
  18. ↑ Akhbari P, Tobin D, Poterlowicz K, Roberts W, Boyne JR (November 2018). "MCV-miR-M1 Targets the Host-Cell Immune Response Resulting in the Attenuation of Neutrophil Chemotaxis" (PDF). The Journal of Investigative Dermatology. 138 (11): 2343–2354. doi: 10.1016/j.jid.2018.03.1527 . PMID   29777657.
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