MicrobiologyBytes

BK virus (BKV) and JC virus (JCV) are widespread human polyomaviruses, and their pathogenic potential during immunodeficiency has been clearly documented. Primary infection usually occurs asymptomatically (or with only mild respiratory symptoms) during childhood, after which the polyomaviruses persist latently in various organs, mainly in the urogenital system, brain and circulating leukocytes. Reactivation of both viruses is common, and frequently associated with asymptomatic viruria. The natural history of infection is well established, but it is still not clear how BKV and JCV are transmitted, although the hypotheses include respiratory, oral-fecal and urinary transmission. Furthermore, on the basis of the frequency of Polyomavirus (PV) infection in childhood, and as has been previously demonstrated in the case of animal homologue polyomaviruses such as the Murine and Simian polyomaviruses (SV-40), some authors have investigated the possibility of vertical transmission, but with conflicting results. So how are these pathogenic viruses transmitted between humans?

Serologic evidence of vertical transmission of JC and BK polyomaviruses in humans. J Gen Virol. Feb 9 2011
Vertical transmission of JC virus and BK virus has been investigated by few authors, with conflicting results. We performed a combined serological and genomic study of 19 unselected pregnant women and their newborns. Blood and urine samples were collected during each gestational trimester in the pregnant women; umbilical cord blood, peripheral blood, urine, and nasopharyngeal secretion samples were taken from newborns at delivery, one week and one month of life. Polyomavirus DNA was detected by nested-PCR. Polyomavirus IgG, IgM and IgA specific antibodies were measured in maternal and newborn serum samples using virus-like particle-based ELISA method. BKV and JCV DNA was detected in urine from 4 (21%) and 5 (26%) women, respectively. BKV and JCV seroprevalence in the pregnant women was 84% and 42%, respectively. Using a rise in the IgG level or the transient appearance of an IgA or IgM response as evidence of infection in the newborn we detected BKV and JCV infections in four (21%) and three (16%) newborns respectively. Three infants had serological evidence of infection with both BKV and JCV. In two of the four possible BKV infected newborns, the mothers seroconverted during pregnancy, while another mother was viruric and IgA seropositive. The mother of one of three possible JCV infected newborn was viruric and IgA seropositive, another mother was viruric. These results suggest JC virus and BK virus can be transmitted from mother to newborn during pregnancy or soon after birth.

Related:

• Solving the mystery of BK virus transmission
• Polyomavirus and Human Merkel Cell Carcinoma
• High prevalence of infection with three new human polyomaviruses

In the past three years, remarkable discoveries have added three new human polyomaviruses (KI virus (KIV), WU virus (WUV) and Merkel cell virus (MCV)) to a class that previously had only two disease-causing members (BK virus (BKV) and JC virus (JCV)) identified. Two monkey polyomaviruses, simian virus (SV)40 and B-cell lymphotropic polyomavirus (LPV) are also present in humans. KIV and WUV lack the agnoprotein coding sequence and regulatory micro (mi)RNA clusters of BKV, JCV and SV40. MCV lacks the agnoprotein sequence but generates miRNAs. KIV, WUV and MCV are all widespread in humans. Although they have distinctive tissue tropisms, all these viruses are probably acquired in childhood. Of these viruses, only MCV has thus far been strongly linked to cancer. Marshalled evidence from diverse sources implicates MCV as an etiological agent of Merkel cell carcinoma. This review compares the structural features of the new and previously known polyomaviruses, with the aim of identifying approaches to molecular pathology.

Structural evaluation of new human polyomaviruses provides clues to pathobiology. Trends Microbiol. 2010 18(5): 215-223

Related:

• High prevalence of infection with three new human polyomaviruses
• Polyomavirus and Human Merkel Cell Carcinoma
• Identification of a Novel Polyomavirus from Patients with Acute Respiratory Tract Infections

BK virus (BKV) belongs to the polyomavirus family and is ubiquitous in the human population. The viral capsid is icosahedral and has a diameter of 45–50 nm. The genome consists of a closed circular double-stranded DNA molecule with approximately 5 kb. BKV infection typically occurs during childhood, without specific symptoms, followed by a state of non-replicative infection in various tissues, with the urogenital tract as the principal site. In the setting of relative or absolute cell-mediated immunosuppression, dramatic increase in BK viral replication occurs, resulting in the lytic destruction of infected uroepithelial cells, which in turn induces the influx of inflammatory immune cells. This destruction of kidney cells most often occurs in 5–8% of kidney transplants resulting in organ loss in half of these cases and is termed BKV-associated nephropathy. Rise in the incidence of Polyomavirus viruria and viremia has been detected in recipients of bone marrow, kidney and heart transplants, as well as an increase in viruria in HIV-infected individuals. The potential for BK replication at distant sites such as the salivary gland may certainly exist in the setting of HIV infection.

While it is clear that BKV infection is an ubiquitous childhood infection, BKV transmission is not currently well understood. The present studies were undertaken to determine whether BKV could infect and replicate within salivary gland cells resulting in virus production and potentially transmission. BKV has been detected in the saliva of patients with HIV-associated salivary gland pathology and in healthy individuals. In order to begin to decipher BKV pathogenesis within the salivary gland cell it was essential to develop an in vitro model system. Submandibular and parotid gland cell lines were able to support virus entry, transcription, translation and virion production and BKV infection could be inhibited by saturating the capsid protein with its ganglioside receptor. This data demonstrates for the first time, BKV detection in saliva and evidence that human salivary gland cells can be productively infected with BK virus. This suggests that while kidney/uroepithelial cells have long been known to be a site of BKV replication and latency, the salivary gland may also constitute an infectious reservoir for BKV. Although the natural route of BKV transmission has not been resolved, this study suggests a potential for oral BKV transmission.

BK virus has tropism for human salivary gland cells in vitro: Implications for transmission. Virology Sep 24 2009
In this study, it was determined that BKV is shed in saliva and an in vitro model system was developed whereby BKV can productively infect both submandibular (HSG) and parotid (HSY) salivary gland cell lines. BKV was detected in oral fluids using quantitative real-time PCR (QRTPCR). BKV infection was determined using quantitative RT-PCR, immunofluorescence and immunoblotting assays. The infectivity of BKV was inhibited by pre-incubation of the virus with gangliosides that saturated the major capsid protein, VP1, halting receptor mediated BKV entry into salivary gland cells. Examination of infected cultures by transmission electron microscopy revealed 45-50 nm BK virions clearly visible within the cells. Subsequent to infection, encapsidated BK virus was detected in the supernatant. We thus demonstrated that BKV was detected in oral fluids and that BK infection and replication occur in vitro in salivary gland cells. These data collectively suggest the potential for BKV oral route of transmission and oral pathogenesis.

Related:

• Polyomavirus and Human Merkel Cell Carcinoma
• High prevalence of infection with three new human polyomaviruses
• Identification of a Novel Polyomavirus from Patients with Acute Respiratory Tract Infections

Polyomaviruses occupy a replicative niche in animals from birds to humans. Two human polyomaviruses, BKV and JCV, were discovered in 1971 and within the last two years, three new polyomaviruses have been found in humans: KI (KIV), WU (WUV), and Merkel Cell (MCV) polyomavirus. MCV was identified in Merkel Cell carcinomas, a rare skin cancer. KIV and WUV were detected in nasal secretions, and may be respiratory viruses. Previously, it had not been determined what percentage of the human population is exposed to KIV, WUV, and MCV, and when initial exposure to these viruses occurs. A new study now suggests that a majority of the human population has been exposed to newly discovered KIV, WUV, and Merkel cell (MCV) human polyomaviruses. The results, based on antibody measurements in serum samples, also suggest that infection with these viruses occurs early in childhood.

In this study, researchers tested over 2220 anonymous donor blood samples (more than 1500 adults and more than 700 young people). They measured antibodies that reacted with specific viral proteins. In addition to KIV, WUV, MCV, BKV, and JCV, two monkey polyomaviruses, SV40 and lymphotropic polyomavirus (LPV), were also studied. Antibodies to LPV were detected in a fraction of people (15%), confirming previous studies suggesting that a relative of this virus may infect humans. The majority of antibodies against SV40 proteins may be attributed to the immune response to BKV. The diseases caused by these viruses remain to be fully described. Future studies will be important to help determine differences in the prevalence of these infections in other geographic areas.

Seroepidemiology of Human Polyomaviruses. 2009 PLoS Pathog 5(3): e1000363
In addition to the previously characterized viruses BK and JC, three new human polyomaviruses (Pys) have been recently identified: KIV, WUV, and Merkel Cell Py (MCV). Using an ELISA employing recombinant VP1 capsid proteins, we have determined the seroprevalence of KIV, WUV, and MCV, along with BKV and JCV, and the monkey viruses SV40 and LPV. Soluble VP1 proteins were used to assess crossreactivity between viruses. We found the seroprevalence (+/- 1%) in healthy adult blood donors (1501) was SV40 (9%), BKV (82%), JCV (39%), LPV (15%), KIV (55%), WUV (69%), MCV strain 350 (25%), and MCV strain 339 (42%). Competition assays detected no sero-crossreactivity between the VP1 proteins of LPV or MCV or between WUV and KIV. There was considerable sero-crossreactivity between SV40 and BKV, and to a lesser extent, between SV40 and JCV VP1 proteins. After correcting for crossreactivity, the SV40 seroprevalence was ~2%. The seroprevalence in children under 21 years of age (n=721) for all Pys was similar to that of the adult population, suggesting that primary exposure to these viruses likely occurs in childhood.

Related:

• Polyomavirus and Human Merkel Cell Carcinoma
• DNA Viruses