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Keywords:

  • Human polyomavirus;
  • immunocompromised;
  • persistent infection;
  • viral coexistence

Abstract

  1. Top of page
  2. Abstract
  3. References

For almost 40 years, polyomavirus JC and BK were the only known human polyomaviruses but in the last 7 years, increased interest and innovative molecular screening techniques have led to the identification of 10 previously unknown polyomaviruses in humans. Two of these, Merkel cell polyomavirus and Trichodysplasia spinulosa polyomavirus, have also been found to cause disease in immunocompromised patients. Seroprevalence studies indicate that human polyomaviruses are transmitted independently of one another in humans and carry different risks of exposure and reexposure throughout life. The potential coexistence of 12 or more different polyomavirus species in the same host and possibly even in the same organ raises the question of potential interactions. Careful review of polyomavirus biology may facilitate new discoveries concerning these formerly underestimated viral agents and their influence on human health.

The identification of human polyomaviruses (HPyV) dates back to 1964, when the neuroscientists Gabriele Zu Rhein and Sam Chou decided to investigate formalin-fixed brain tissue sections from patients with progressive multifocal leukoencephalopathy by electron microscopy, a novel technique at that time [1]. In the nucleus of oligodendrocytes, numerous non-enveloped viral particles of 40–45 nm diameter were seen, either dispersed or arranged in filamentous or crystal-like arrays. 6 years later, virus isolation was successful from diseased brain tissue of the patient J. C., whose initials the virus has carried since [2]. Independently, in the same year, another polyomavirus was identified by electron micro-scopy of cytopathically altered urinary epithelial cells shed by a kidney transplant patient B.K. This virus was also isolated by cell culture and named according to the patient's initials [3]. Although the link between JC polyomavirus (JCPyV) and progressive multifocal leuko encephalopathy was readily confirmed, BK polyomavirus (BKPyV) remained an ‘orphan’ until the observation of its association with hemorrhagic cystitis in allogeneic hematopoietic stem cell transplant patients [4] and nephropathy/interstitial nephritis in kidney transplant patients [5]. The delineation of the sequence of viruria, viremia, and organ invasive disease provided a new paradigm for screening and monitoring of patients at risk [6, 7], and led to the discovery of selective intrapatient emergence of more virulent polyoma-virus mutants in real time [8]. Following the wave of the HIV pandemic, the evolution of transplant medicine, the increasing general life expectancy, and the introduction of targeted immunomodulatory therapy for autoimmune diseases have collectively increased the number of individuals affected by polyomavirus diseases [9-12].

For almost 40 years, JCPyV and BKPyV were the only known human polyomaviruses but in the last 5 years, increased interest and innovative molecular screening techniques have led to the identification of 10 previously unknown polyomaviruses in humans, some of which are also found to cause disease in immunocompromised individuals. In this special issue, an update on human polyomaviruses is presented, starting with JCPyV [13] and BKPyV [14], summarizing the accumulated knowledge about our most thoroughly studied human polyomaviruses.

Babakir-Mina and colleagues then report on Karolinska Institutet polyomavirus (KIPyV) and Washington University polyomavirus (WUPyV) [15] identified in airway samples from patients with respiratory disease [16, 17]. Although the context of this discovery may suggest an association with severe respiratory disease, the influence of these viruses on human health remains to be defined.

Coursaget and colleagues focus on Merkel cell carcinoma virus (MCPyV) [18], a virus detected in tumor cells of Merkel cell carcinoma (MCC), an aggressive cutaneous skin cancer mainly affecting immunocompromised individuals [19]. There is increasing epidemiological and mechanistic evidence for a role of MCPyV in MCC. In almost every case of MCC, the MCPyV genome is clonally integrated into the chromosomal DNA of the carcinoma cells, leading to a truncation of the viral protein large T antigen (LTag) and thereby inhibiting initiation of MCPyV genome replication. Interestingly, small T antigen (sTag) remains intact and is believed to play a key transforming role in MCC.

Kazem and colleagues describe the discovery of Trichodysplasia spinulosa polyomavirus (TsPyV) [20] that was identified in a rare skin disease characterized by the striking development of keratin spicules originating from aberrant hair follicles in immunocompromised patients [21]. An overview over all reported cases of T. spinulosa is given, the characteristics of TSPyV are compared with other HPyV of the skin and the evidence for its etiological role in T. spinulosa is presented.

Ehlers and Wieland provide an update on HPyV6, HPyV7, HPyV9, HPyV10, HPyV12, and Saint Louis polyomavirus (STLPyV) [22] and their phylogenetic relationships, contrasting with other known human and non-human PyVs. Whereas HPyV6 and HPyV7 were first detected on skin of healthy subjects [23], HPyV9 was found is a serum sample of a kidney transplant patient [24]. HPyV10 was identified in papillomavirus-induced anal condylomata [25] and the Malawi polyomavirus (MWPyV) and the MX polyomavirus (MXPyV), both identified in stool samples, are variants of HPyV10 [26, 27]. The closely related but distinct STLPyV was detected in stool samples from diarrhea-inflicted and healthy children [28] while HPyV12 was identified in liver tissue [29]. So far, no association with disease has been found for any of these viruses.

Remarkably, seroprevalence studies have shown that all human polyomaviruses evaluated so far, infect a large proportion of the human population globally. However, differing age-dependence patterns of seroprevalence have been described. For MCPyV, the seroprevalence increases rapidly during childhood and then remains rather constant throughout life; for JCPyV, the seroprevalence increases slowly during childhood and continues to increase throughout adult life; for BKPyV, the seroprevalence increases rapidly during childhood, but declines after the age of 40 [29-32]. These differences suggest that polyomaviruses are transmitted independently of one another in humans and carry different risks of exposure and reexposure throughout life.

The potential coexistence of 12 or more different polyomavirus species in the same host and possibly even in the same organ raises the question of potential interactions. An inhibitory virological or immunological interaction between BKPyV and JCPyV has already been suggested [30, 33] whereas in vitro studies have shown that SV40 LTag can positively influence both BKPyV and JCPyV replication [34]. Hopefully, the expert reviews in this special issue will help to update and disseminate key virological and medical knowledge of polyomavirus biology, and facilitate new discoveries concerning these formerly underestimated viral agents and their influence on human health.

References

  1. Top of page
  2. Abstract
  3. References
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