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Concept: Polyomavirus

173

In recent years the incidence of male infertility has increased. Many risk factors have been taken into consideration, including viral infections. Investigations into viral agents and male infertility have mainly been focused on human papillomaviruses, while no reports have been published on polyomaviruses and male infertility. The aim of this study was to verify whether JC virus and BK virus are associated with male infertility. Matched semen and urine samples from 106 infertile males and 100 fertile males, as controls, were analyzed. Specific PCR analyses were carried out to detect and quantify large T (Tag) coding sequences of JCV and BKV. DNA sequencing, carried out in Tag JCV-positive samples, was addressed to viral protein 1 (VP1) coding sequences. The prevalence of JCV Tag sequences in semen and urine samples from infertile males was 34% (72/212), whereas the BKV prevalence was 0.94% (2/212). Specifically, JCV Tag sequences were detected in 24.5% (26/106) of semen and 43.4% (46/106) of urine samples from infertile men. In semen and urine samples from controls the prevalence was 11% and 28%, respectively. A statistically significant difference (p<0.05) in JCV prevalence was disclosed in semen and urine samples of cases vs. controls. A higher JC viral DNA load was detected in samples from infertile males than in controls. In samples from infertile males the JC virus type 2 strain, subtype 2b, was more prevalent than ubiquitous type 1. JCV type 2 strain infection has been found to be associated with male infertility. These data suggest that the JC virus should be taken into consideration as an infectious agent which is responsible for male infertility.

Concepts: DNA, Infectious disease, Microbiology, Virus, Infection, BK virus, JC virus, Polyomavirus

169

Since their discovery in 1971, the polyomaviruses JC (JCPyV) and BK (BKPyV), isolated from patients with progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy, respectively, remained for decades as the only known members of the Polyomaviridae family of viruses of human origin. Over the past five years, the application of new genomic amplification technologies has facilitated the discovery of several novel human polyomaviruses (HPyVs), bringing the present number to 10. These HPyVs share many fundamental features in common such as genome size and organization. Infection by all HPyVs is widespread in the human population, but they show important differences in their tissue tropism and association with disease. Much remains unknown about these new viruses. In this review, we discuss the problems associated with studying HPyVs, such as the lack of culture systems for the new viruses and the gaps in our basic understanding of their biology. We summarize what is known so far about their distribution, life cycle, tissue tropism, their associated pathologies (if any), and future research directions in the field.

Concepts: Human genome, Biology, Virus, Genome, Pathology, Progressive multifocal leukoencephalopathy, JC virus, Polyomavirus

149

BK virus (BKV) is a non-enveloped DNA virus of the polyomaviridae family that causes an interstitial nephritis in immunosuppressed patients. BKV nephropathy is now a leading cause of chronic kidney disease and early allograft failure following kidney transplantation. It is also known to cause renal disease with a progressive decline in kidney function in non-renal solid organ transplant (NRSOT) recipients, although the disease may not be recognized nor its impact appreciated in this patient population. In this report, we review the existing literature to highlight our current understanding of its incidence in NRSOT populations, the approaches to diagnosis and the potential treatment options.

Concepts: Chronic kidney disease, Kidney, Nephrology, Organ, Organ transplant, Kidney transplantation, JC virus, Polyomavirus

28

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

Concepts: AIDS, Multiple sclerosis, Oligodendrocyte, Progressive multifocal leukoencephalopathy, JC virus, Rituximab, Polyomavirus, Natalizumab

28

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. The majority of MCC (70-80%) harbor clonally integrated Merkel cell polyomavirus (MCV) in the tumor genome and express viral T antigen oncoproteins. The characterization of an early passage MCV-positive MCC cell line MS-1 is described, and its cellular, immunohistochemical, and virological features to MCV-negative (UISO, MCC13, and MCC26) and MCV-positive cell lines (MKL-1 and MKL-2) were compared. The MS-1 cellular genome harbors integrated MCV, which preserves an identical viral sequence from its parental tumor. Neither VP2 gene transcripts nor VP1 protein are detectable in MS-1 or other MCV-positive MCC cell lines tested. Mapping of viral and cellular integration sites in MS-1 and MCC tumor samples demonstrates no consistent viral or cellular gene integration locus. All MCV-positive cell lines show cytokeratin 20 positivity and grow in suspension. When injected subcutaneously into NOD scid gamma (NSG) mice, MS-1 forms a discrete macroscopic tumor. Immunophenotypic analysis of the MS-1 cell line and xenografts in mice show identical profiles to the parental tumor biopsy. Hence, MS-1 is an early passage cell line that provides a useful in vitro model to characterize MCV-positive MCC.

Concepts: Protein, Gene, Cell, Cancer, Mortality rate, Merkel cell cancer, Polyomavirus, Merkel cell polyomavirus

28

Abstract Objective. BK virus (BKV)-induced viraemia after renal transplantation can be associated with severe impairment of graft function. This study evaluated possible risk factors for BKV replication and examined the outcomes following various currently used treatment approaches. Material and methods. Fifty-seven renal transplant recipients with BKV viraemia were retrospectively compared with 71 BKV-negative recipients to identify risk factors for BKV viraemia. Furthermore, outcome and graft function in 14 patients with BKV replication, in whom mycophenolate mofetil (MMF) was discontinued with a dose reduction of the remaining immunosuppressants, were compared with 32 patients in whom both MMF and the additional immunosuppressants were reduced. Results. Patients with BKV viraemia received MMF (p < 0.01) and triple immunosuppression (p < 0.01) significantly more often, and displayed tacrolimus (p = 0.034) at higher blood concentrations (p = 0.002), a lower lymphocyte count (p = 0.006) and a longer warm ischaemic time (p = 0.019), and were more often male (p = 0.026). Patients in whom MMF was stopped had a higher chance of clearance of BKV viraemia (p = 0.022), which was achieved more rapidly (p = 0.048). Graft function improved during treatment and no graft losses occurred, compared with eight graft losses in the MMF-treated group (p = 0.04). Conclusions. MMF and tacrolimus could promote BKV viraemia after renal transplantation. Discontinuation of MMF together with a reduction of calcineurin inhibitors and glucocorticoids could be an option to reduce BKV replication after renal transplantation.

Concepts: Kidney, Organ transplant, Kidney transplantation, Immunosuppressive drug, BK virus, JC virus, Mycophenolic acid, Polyomavirus

28

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy linked to a contributory virus (Merkel cell polyomavirus). Multiple epidemiologic studies have established an increased incidence of MCC among persons with systemic immune suppression. Several forms of immune suppression are associated with increased MCC incidence, including hematologic malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplant. Indeed, immune-suppressed individuals represent ∼10% of MCC patients, a significant overrepresentation relative to the general population. We hypothesized that immune-suppressed patients may have a poorer MCC-specific prognosis and examined a cohort of 471 patients with a combined follow-up of 1,427 years (median 2.1 years). Immune-suppressed patients (n=41) demonstrated reduced MCC-specific survival (40% at 3 years) compared with patients with no known systemic immune suppression (n=430; 74% MCC-specific survival at 3 years). By competing risk regression analysis, immune suppression was a stage-independent predictor of worsened MCC-specific survival (hazard ratio 3.8, P<0.01). Thus, immune-suppressed individuals have both an increased chance of developing MCC and poorer MCC-specific survival. It may be appropriate to follow these higher-risk individuals more closely, and, when clinically feasible, there may be a benefit of diminishing iatrogenic systemic immune suppression.Journal of Investigative Dermatology advance online publication, 29 November 2012; doi:10.1038/jid.2012.388.

Concepts: Immune system, Epidemiology, Cancer, Immunology, Immunosuppressive drug, Merkel cell cancer, Polyomavirus, Merkel cell polyomavirus

27

The use of natalizumab has likely been limited by its association with progressive multifocal leukoencephalopathy (PML), an infection caused by the human polyomavirus John Cunningham (JC). Three factors were recently identified that contribute to the overall risk of natalizumab-associated PML: (1) Positive serostatus for anti-JCV antibodies, (2) prior use of immunosuppressants, and (3) duration of natalizumab therapy. This risk stratification algorithm has not led to a reduction in the incidence of PML in natalizumab-treated patients with multiple sclerosis between April 2010 and February 2014. This observation may appear perplexing, as treatment duration and JCV serostatus are modifiable risk factors. Potential reasons for the lack of success of companion diagnostics that determine the overall risk of natalizumab-associated PML are discussed.

Concepts: Multiple sclerosis, Oligodendrocyte, Progressive multifocal leukoencephalopathy, Progressive lens, JC virus, Rituximab, Polyomavirus, Natalizumab

27

Polyomaviruses are ubiquitous, species-specific viruses belonging to the family Papovaviridae. The two most commonly known human polyomaviruses, BK virus and JC virus were first described in the 1970s. Newer human polyomaviruses, namely KI polyoma virus, WU polyoma virus and Merkel cell polyoma virus were identified in the last five years. Most humans encounter BK and JC virus during childhood, causing mild illness. However, when reactivated or acquired in the immunocompromised host, BK and JC virus have been implicated in a number of human clinical disease states. BK is most commonly associated with renal involvement, such as ureteral stenosis, hemorrhagic cystitis and nephropathy. Less commonly, it is associated with pneumonitis, retinitis, liver disease and meningoencephalitis. JC virus is most well known for its association with progressive multifocal leukoencephalopathy, and is possibly implicated in the development of various human neoplasms. The following chapter will outline the basic virology, epidemiology and clinical manifestations of BK and JC virus and discuss relevant diagnostic and treatment options.

Concepts: AIDS, Virus, Viruses, Progressive multifocal leukoencephalopathy, BK virus, JC virus, Polyomavirus, Polyomaviruses

27

A 69-year old man presents with a subacute history of worsening confusion, anxiety and abnormal gait. Brain MRI revealed an extensive non-enhancing signal abnormality of parieto-occipito-temporal white matter. CSF PCR was positive for JC virus, suggestive of progressive multifocal leukoencephalopathy (PML). Extensive workup for occult immunosuppression was negative. Although PML in an immunocompetent patient is exceedingly rare, biopsy confirmed the diagnosis. Mirtazapine and mefloquine therapies were initiated and JCV DNA titre decreased by 100-fold at six months. One year later, his clinical course had stabilized and neuroimaging was improved. Our case suggests that PML can rarely afflict immunocompetent individuals and that serotonin receptor targeting pharmacological therapy may improve the outcome.

Concepts: AIDS, Protein, Medicine, Serotonin, Progressive multifocal leukoencephalopathy, JC virus, Polyomavirus, 5-HT2C receptor