Dynamics of urinary polyomavirus shedding in healthy adult women

Kling, Courtney L.; Wright, Alexandra T.; Katz, Sophie; McClure, Gloria B.; Gardner, Jay; Williams, Jason T.; Meinerz, Natalie M.; Garcea, Robert L.; Vanchiere, John A.

doi:10.1002/jmv.23319

Cited by 23 publications

(18 citation statements)

References 16 publications

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“…BKV is episodically shed in the urine (32,33). Unfortunately, due to their extremely low frequencies in the circulation, we could not perform an ex vivo characterization of BKV LTAg-specific CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 ⁺ T Cells in Healthy Adults

Aalderen

Remmerswaal

Heutinck

et al. 2013

J Virol

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The human polyomavirus BK virus (BKV) establishes a latent and asymptomatic infection in the majority of the population. In immunocompromised individuals, the virus frequently (re)activates and may cause severe disease such as interstitial nephritis and hemorrhagic cystitis. Currently, the therapeutic options are limited to reconstitution of the antiviral immune response. T cells are particularly important for controlling this virus, and T cell therapies may provide a highly specific and effective mode of treatment. However, little is known about the phenotype and function of BKV-specific T cells in healthy individuals. Using tetrameric BKV peptide-HLA-A02 complexes, we determined the presence, phenotype, and functional characteristics of circulating BKV VP1-specific CD8 ؉ T cells in 5 healthy individuals. We show that these cells are present in low frequencies in the circulation and that they have a resting CD45RA ؊ CD27 ؉ memory and predominantly CCR7 ؊ CD127 ؉ KLRG1 ؉ CD49d hi CXCR3 hi T-bet int Eomesodermin lo phenotype. Furthermore, their direct cytotoxic capacity seems to be limited, since they do not readily express granzyme B and express only little granzyme K. We compared these cells to circulating CD8 ؉ T cells specific for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and influenza virus (Flu) in the same donors and show that BKV-specific T cells have a phenotype that is distinct from that of CMV-and EBV-specific T cells. Lastly, we show that BKV-specific T cells are polyfunctional since they are able to rapidly express interleukin-2 (IL-2), gamma interferon (IFN-␥), tumor necrosis factor ␣, and also, to a much lower extent, MIP-1␤ and CD107a. In healthy individuals, the polyomavirus BK virus (BKV) establishes a latent, or "smoldering," but asymptomatic infection. However, in immunocompromised individuals, the virus frequently escapes the normal immunological surveillance to become systemically active, after which it may cause severe pathology. BKV elicits interstitial nephritis of the allograft in about 5% of kidney transplant recipients, making it an important cause of graft failure and graft loss. In up to 30% of hematopoietic stem cell transplant (HSCT) recipients, the virus induces hemorrhagic cystitis, thereby significantly contributing to morbidity and length of hospitalization (1).Currently, the main mode of therapy for patients suffering from BKV infection comprises reconstitution of the immunological antiviral response. In solid organ transplant recipients, this is achieved through tapering of the immunosuppressive medication. Unfortunately, this comes at the cost of increased allograft rejection, and in HSCT recipients this is an unattractive approach due to a considerable increase in the risk of graft-versus-host disease. So far, antiviral agents, such as cidofovir and leflunomide, have shown little effect on BKV replication in vivo (1). It is therefore crucial to develop new modes of therapy. In this regard, the normal T cell response was shown to be very important for keeping BKV at b...

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Section: Discussionmentioning

confidence: 99%

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 ⁺ T Cells in Healthy Adults

Aalderen

Remmerswaal

Heutinck

et al. 2013

J Virol

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“…The menstrual cycle had no apparent impact on urinary JCPyV shedding in a longitudinal study of daily sampling, covering 36 complete menstrual cycles of 20 healthy immunocompetent women (mean age 25.8 AE 3.1 years), but more than half of the participants reported to use hormonal contraception (139). Antibodies to JCPyV were found in 6 women (30%), 2 (33%), of whom were shedding JCPyV (one continuously, one in 15% of the samples).…”

Section: Jcpyv Replicationmentioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

149

169

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JC polyomavirus (JCPyV) was the first of now 12 PyVs detected in humans, when in 1964, PyV particles were revealed by electron microscopy in progressive multifocal leukoencephalopathy (PML) tissues. JCPyV infection is common in 35–70% of the general population, and the virus thereafter persists in the renourinary tract. One third of healthy adults asymptomatically shed JCPyV at approximately 50 000 copies/mL urine. PML is rare having an incidence of <0.3 per 100 000 person years in the general population. This increased to 2.4 per 1000 person years in HIV‐AIDS patients without combination antiretroviral therapy (cART). Recently, PML emerged in multiple sclerosis patients treated with natalizumab to 2.13 cases per 1000 patients. Natalizumab blocks α4‐integrin‐dependent lymphocyte homing to the brain suggesting that not the overall cellular immunodeficiency but local failure of brain immune surveillance is a pivotal factor for PML. Recovering JCPyV‐specific immune control, e.g., by starting cART or discontinuing natalizumab, significantly improves PML survival, but is challenged by the immune reconstitution inflammatory syndrome. Important steps of PML pathogenesis are undefined, and antiviral therapies are lacking. New clues might come from molecular and functional profiling of JCPyV and PML pathology and comparison with other replicative pathologies such as granule cell neuronopathy and (meningo‐)encephalitis, and non‐replicative JCPyV pathology possibly contributing to some malignancies. Given the increasing number of immunologically vulnerable patients, a critical reappraisal of JCPyV infection, replication and disease seems warranted.

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“…After primary infection, BKPyV latently persists in the urothelium and renal tubular cells (5,6), and small amounts of viral progeny can be temporarily detected in urine of 7-55% of healthy persons, depending on the sampling frequency (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…BK polyomavirus (BKPyV) causes asymptomatic infection early in life (1,2), reaching a seroprevalence of %90% in adults (3,4). After primary infection, BKPyV latently persists in the urothelium and renal tubular cells (5,6), and small amounts of viral progeny can be temporarily detected in urine of 7-55% of healthy persons, depending on the sampling frequency (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Pretransplantation Donor–Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation

Wunderink

Meijden

Brouwer

et al. 2017

American Journal of Transplantation

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Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV‐associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor–recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high–BKPyV‐seroreactive donors with low‐seroreactive recipients resulted in a 10‐fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5–29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.

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Dynamics of urinary polyomavirus shedding in healthy adult women

Cited by 23 publications

References 16 publications

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 ⁺ T Cells in Healthy Adults

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 ⁺ T Cells in Healthy Adults

The human JC polyomavirus (JCPyV): virological background and clinical implications

Pretransplantation Donor–Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation

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Dynamics of urinary polyomavirus shedding in healthy adult women

Cited by 23 publications

References 16 publications

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 + T Cells in Healthy Adults

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 + T Cells in Healthy Adults

The human JC polyomavirus (JCPyV): virological background and clinical implications

Pretransplantation Donor–Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation

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Product

Resources

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Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 ⁺ T Cells in Healthy Adults

Phenotypic and Functional Characterization of Circulating Polyomavirus BK VP1-Specific CD8 ⁺ T Cells in Healthy Adults