The Role of Merkel Cell Polyomavirus and Other Human  Polyomaviruses in Emerging Hallmarks of Cancer

Moens, Ugo; Rasheed, Kashif; Abdulsalam, Ibrahim; Sveinbjørnsson, Baldur

doi:10.3390/v7041871

Cited by 42 publications

(51 citation statements)

References 213 publications

(234 reference statements)

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“…Note that A3A mRNA was detected but at too low a level to be graphed in panel A. **, P Ͻ 0.01; ****, P Ͻ 0.0001. since these viruses have oncogenic potential (33). Using BKPyV and an established primary renal proximal tubule epithelial (RPTE) cell culture system (24, 25), we determined whether virus infection alters A3 gene expression (Fig.…”

Section: Figmentioning

confidence: 99%

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

Verhalen

Starrett

Harris

et al. 2016

J Virol

106

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The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis. IMPORTANCEPolyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virusinduced tumorigenesis. P olyomaviruses (PyVs) are a family of small nonenveloped viruses containing an ϳ5-kb circular double-stranded DNA genome. Most human PyVs establish a subclinical persistent infection in healthy individuals (1). These viruses can reactivate under various immunosuppression conditions and cause a variety of severe diseases, including cancers (2). Among them, BK polyomavirus (BKPyV) reactivation is a major concern in kidney and bone marrow transplant patients due to the possibility of development of polyomavirus-associated nephropathy and hemorrhagic cystitis, respectively (3). Recently, there have also been increasing reports demonstrating an association between BKPyV infection and the occurrence of renourinary tumors (4). JC polyomavirus (JCPyV) reactivation can lead to progressive multifocal leu...

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Section: Figmentioning

confidence: 99%

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

Verhalen

Starrett

Harris

et al. 2016

J Virol

106

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“…Many of these viruses manifest with high morbidity and mortality, particularly in the immunocompromised and young. Epstein-Barr virus (EBV), 2 Kaposi sarcoma-associated herpesvirus (KSHV), human papillomavirus, hepatitis B virus, and Merkel cell polyomavirus are responsible for a staggering majority of virus-associated human cancers globally (1)(2)(3). Human papillomavirus is considered the most prevalent sexually transmitted pathogen in the United States (4).…”

Section: The Impact Of Nuclear Replicating Dna Viruses On Human Healthmentioning

confidence: 99%

The Emerging Role of Nuclear Viral DNA Sensors

Diner

Lum

Cristea

2015

Journal of Biological Chemistry

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Detecting pathogenic DNA by intracellular receptors termed "sensors" is critical toward galvanizing host immune responses and eliminating microbial infections. Emerging evidence has challenged the dogma that sensing of viral DNA occurs exclusively in sub-cellular compartments normally devoid of cellular DNA. The interferon-inducible protein IFI16 was shown to bind nuclear viral DNA and initiate immune signaling, culminating in antiviral cytokine secretion. Here, we review the newly characterized nucleus-originating immune signaling pathways, their links to other crucial host defenses, and unique mechanisms by which viruses suppress their functions. We frame these findings in the context of human pathologies associated with nuclear replicating DNA viruses.Existing under the constant risk of invasion by pathogenic microorganisms, mammalian cells employ an array of constitutively expressed, germ-line-encoded receptors to survey the intra-and extracellular milieu for pathogen-or damage-associated molecules. Binding of these cellular receptors to their specific ligands evokes intracellular immune signaling cascades that culminate in the robust expression and secretion of antiviral cytokines, such as type I interferons (IFNs). Upon their release from the cell, these induced signaling factors operate in both an autocrine and a paracrine manner, inciting nearby cells to assume antiviral transcriptional programs. Cytokines further stimulate mammalian innate and adaptive immune responses, including the recruitment of antigen-presenting or cytotoxic leukocytes and the production of microbe-specific antibodies. Altogether, these cytokine-coordinated events promote the elimination of the invading pathogen. Thus, the molecular mechanisms mediating the recognition of and response to microbial molecular signatures are critically important.The DNA genomes of DNA viruses, a class of prevalent human pathogens, serve as one such immunogenic molecular signature. For preventing spurious auto-activation with cellular "self" DNA, the intracellular surveillance of viral DNA was thought to occur exclusively in cytosolic and endosomal compartments. However, this model fails to reconcile the fact that nearly all DNA viruses deposit and replicate their DNA genomes exclusively within host nuclei. As part of a shifting paradigm, recent studies have established the existence of cellular DNA sensors that detect viral DNA within the nucleus to trigger immune signaling. Here, we review the recent discoveries and ongoing challenges within the emerging field of nuclear DNA sensing.

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“…Viral DNA has also been detected in the respiratory tract, saliva, urine and the gastrointestinal system, suggesting possible fecal-oral transmission [14]. Fascinatingly, MCPyV is currently the only human polyomavirus known to be oncogenic, despite numerous studies investigating the carcinogenic potential of the 12 other human polyomaviruses [19].…”

mentioning

confidence: 99%

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

Vandeven

Nghiem

2016

Immunotherapy

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Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (∼80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virusnegative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immunebased approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

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The Role of Merkel Cell Polyomavirus and Other Human Polyomaviruses in Emerging Hallmarks of Cancer

Cited by 42 publications

References 213 publications

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

The Emerging Role of Nuclear Viral DNA Sensors

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

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