Human Polyomavirus 9 Infection in Kidney Transplant Patients - Volume 20, Number 6—June 2014 - Emerging Infectious Disease journal - CDC

full-text ►

Human Polyomavirus 9 Infection in Kidney Transplant Patients - Volume 20, Number 6—June 2014 - Emerging Infectious Disease journal - CDC

Volume 20, Number 6—June 2014

Research

Human Polyomavirus 9 Infection in Kidney Transplant Patients

Article Contents

• Materials and Methods
• Results
• Discussion
• Acknowledgments
• References
• Figure 1
• Figure 2
• Figure 3
• Figure 4
• Table 1
• Table 2
• Technical Appendix - 231 KB 
• Suggested Citation

Els van der Meijden , Herman F. Wunderink, Caroline S. van der Blij-de Brouwer, Hans L. Zaaijer, Joris I. Rotmans, Jan Nico Bouwes Bavinck, and Mariet C.W. Feltkamp

Author affiliations: Leiden University Medical Center, Leiden, the Netherlands (E. van der Meijden, H.F. Wunderink, C.S. van der Blij-de Brouwer, J.I. Rotmans, J.N. Bouwes Bavinck, M.C.W. Feltkamp); Sanquin Blood Supply Foundation, Amsterdam, the Netherlands (H.L. Zaaijer)

Suggested citation for this article

Abstract

Several human polyomaviruses of unknown prevalence and pathogenicity have been identified, including human polyomavirus 9 (HPyV9). To determine rates of HPyV9 infection among immunosuppressed patients, we screened serum samples from 101 kidney transplant patients in the Netherlands for HPyV9 DNA and seroreactivity. A total of 21 patients had positive results for HPyV9 DNA; positivity rates peaked at 3 months after transplantation, but the highest viral loads were measured just after transplantation. During 18 months of follow-up, HPyV9 seroprevalence increased from 33% to 46% among transplant patients; seroprevalence remained stable at ≈30% in a control group of healthy blood donors in whom no HPyV9 DNA was detected. Further analysis revealed an association between detection of HPyV9 and detection of BK polyomavirus but not of cytomegalovirus. Our data indicate that HPyV9 infection is frequent in kidney transplant patients, but the nature of infection—endogenous or donor-derived—and pathogenic potential of this virus remain unknown.

The Polyomaviridae constitute a family of small DNA viruses that infect a variety of hosts. BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV), discovered in 1971 (1,2), are well-known examples of human polyomaviruses (HPyVs) that cause severe disease in immunocompromised patients. Serologic data have revealed that most polyomaviruses are ubiquitous (3–6). In case of JCPyV and BKPyV, primary infection occurs early in life, without apparent symptoms, and persists throughout life as latent infection in the kidneys, accompanied by occasional virus shedding in urine (7). When immunity is decreased, these viruses can reactivate with detectable viremia and manifestation of disease, which poses a threat to, among others, patients who receive solid-organ transplants. For kidney transplant patients, BKPyV infection is considered the most common viral complication and causes nephropathy and graft loss in 1%–10% of cases if left untreated (8). It is not known what determines the severity of BKPyV infection and whether co-infection is involved in the pathogenesis.

Since 2007, at least 10 novel HPyVs have been discovered (9–20); of these, Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa–associated polyomavirus (TSPyV) have been shown to be associated with disease (11,19,21,22). Human polyomavirus 9 (HPyV9), so far without a disease association, was identified in 2011 from a serum sample from a kidney transplant patient (17). Overall seroprevalence of HPyV9 has been determined to be 25% to 50% (23–26).

Because HPyV9 was originally isolated from a kidney transplant recipient (17), we aimed to systematically study the presence of HPyV9 infection in kidney transplant patients and investigate a possible association with the known nephropathogenic BKPyV. We analyzed a cohort of 101 transplant patients who received either a kidney transplant or a simultaneous kidney–pancreas transplant for the appearance of markers for HPyV9 infection during the 18 months after transplantation. We assessed the presence of HPyV9 DNA and IgG seroresponses in serum samples. The HPyV9 findings in the transplant cohort were compared with those obtained for an age- and sex-matched cohort of healthy blood donors. Co-infection with BKPyV was investigated by comparing observed HPyV9 and BKPyV viremia levels in the transplant cohort. For comparative purposes, we also tested for cytomegalovirus (CMV), which, like polyomaviruses, frequently reactivates during immunosuppressive drug use after transplantation.

Acknowledgments

We thank Eric Claas for designing primers and probes of the HPyV9 and BKPyV PCR and Ann Vossen for fruitful discussions.

This work was supported in part by Dutch Kidney Foundation grant WO 2013.06/13A1D302.

References

1. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971;297:1253–7. DOIPubMed
2. Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet.1971;297:1257–60 . DOIPubMed
3. Carter JJ, Paulson KG, Wipf GC, Miranda D, Madeleine MM, Johnson LG, Association of Merkel cell polyomavirus–specific antibodies with Merkel cell carcinoma. J Natl Cancer Inst. 2009;101:1510–22. DOIPubMed
4. Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis.2009;199:837–46. DOIPubMed
5. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog. 2009;5:e1000363. DOIPubMed
6. van der Meijden E, Kazem S, Burgers MM, Janssens R, Bouwes Bavinck JN, de Melker H,Seroprevalence of trichodysplasia spinulosa–associated polyomavirus. Emerg Infect Dis.2011;17:1355–63 .PubMed
7. Gjoerup O, Chang Y. Update on human polyomaviruses and cancer. Adv Cancer Res.2010;106:1–51. DOIPubMed
8. Hirsch HH, Randhawa P. BK polyomavirus in solid organ transplantation. Am J Transplant.2013;13(Suppl 4):179–88. DOIPubMed
9. Allander T, Andreasson K, Gupta S, Bjerkner A, Bogdanovic G, Persson MA, Identification of a third human polyomavirus. J Virol. 2007;81:4130–6 . DOIPubMed
10. Buck CB, Phan GQ, Raiji MT, Murphy PM, McDermott DH, McBride AA. Complete genome sequence of a tenth human polyomavirus. J Virol. 2012;86:10887. DOIPubMed
11. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–100. DOIPubMed
12. Gaynor AM, Nissen MD, Whiley DM, Mackay IM, Lambert SB, Wu G, Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog.2007;3:e64. DOIPubMed
13. Korup S, Rietscher J, Calvignac-Spencer S, Trusch F, Hofmann J, Moens U, Identification of a novel human polyomavirus in organs of the gastrointestinal tract. PLoS ONE.2013;8:e58021. DOIPubMed
14. Lim ES, Reyes A, Antonio M, Saha D, Ikumapayi UN, Adeyemi M, Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing. Virology. 2013;436:295–303. DOIPubMed
15. Sauvage V, Foulongne V, Cheval J, Ar GM, Pariente K, Dereure O, Human polyomavirus related to African green monkey lymphotropic polyomavirus. Emerg Infect Dis.2011;17:1364–70 .PubMed
16. Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe. 2010;7:509–15. DOIPubMed
17. Scuda N, Hofmann J, Calvignac-Spencer S, Ruprecht K, Liman P, Kuhn J, A novel human polyomavirus closely related to the African green monkey–derived lymphotropic polyomavirus (LPV). J Virol. 2011;85:4586–90. DOIPubMed
18. Siebrasse EA, Reyes A, Lim ES, Zhao G, Mkakosya RS, Manary MJ, Identification of MW polyomavirus, a novel polyomavirus in human stool. J Virol. 2012;86:10321–6 . DOIPubMed
19. van der Meijden E, Janssens RW, Lauber C, Bouwes Bavinck JN, Gorbalenya AE,Feltkamp MC. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog. 2010;6:e1001024. DOIPubMed
20. Yu G, Greninger AL, Isa P, Phan TG, Martinez MA, de la Luz SM, Discovery of a novel polyomavirus in acute diarrheal samples from children. PLoS ONE. 2012;7:e49449. DOIPubMed
21. Kazem S, van der Meijden E, Kooijman S, Rosenberg AS, Hughey LC, Browning JC,Trichodysplasia spinulosa is characterized by active polyomavirus infection. J Clin Virol.2012;53:225–30. DOIPubMed
22. Shuda M, Arora R, Kwun HJ, Feng H, Sarid R, Fernandez-Figueras MT, Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer. 2009;125:1243–9. DOIPubMed
23. Nicol JT, Touze A, Robinot R, Arnold F, Mazzoni E, Tognon M, Seroprevalence and cross-reactivity of human polyomavirus 9. Emerg Infect Dis. 2012;18:1329–32 . DOIPubMed
24. Nicol JT, Robinot R, Carpentier A, Carandina G, Mazzoni E, Tognon M, Age-specific seroprevalence of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9 and trichodysplasia Spinulosa–associated polyomavirus. Clin Vaccine Immunol.2013;20:363–8. DOIPubMed
25. Trusch F, Klein M, Finsterbusch T, Kuhn J, Hofmann J, Ehlers B. Seroprevalence of human polyomavirus 9 and cross-reactivity to African green monkey–derived lymphotropic polyomavirus. J Gen Virol. 2012;93:698–705 . DOIPubMed
26. van der Meijden E, Bialasiewicz S, Rockett RJ, Tozer SJ, Sloots TP, Feltkamp MC. Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin. PLoS ONE. 2013;8:e81078. DOIPubMed
27. Antonsson A, Waterboer T, Bouwes Bavinck JN, Abeni D, de Koning M, Euvrard S,Longitudinal study of seroprevalence and serostability of 34 human papillomavirus types in European organ transplant recipients. Virology. 2013;436:91–9. DOIPubMed
28. Niesters HG. Quantitation of viral load using real-time amplification techniques. Methods.2001;25:419–29 . DOIPubMed
29. Kalpoe JS, Kroes AC, de Jong MD, Schinkel J, de Brouwer CS, Beersma MF, Validation of clinical application of cytomegalovirus plasma DNA load measurement and definition of treatment criteria by analysis of correlation to antigen detection. J Clin Microbiol.2004;42:1498–504. DOIPubMed
30. Waterboer T, Sehr P, Michael KM, Franceschi S, Nieland JD, Joos TO, Multiplex human papillomavirus serology based on in situ–purified glutathione S–transferase fusion proteins. Clin Chem. 2005;51:1845–53. DOIPubMed
31. Csoma E, Sapy T, Meszaros B, Gergely L. Novel human polyomaviruses in pregnancy: higher prevalence of BKPyV, but no WUPyV, KIPyV and HPyV9. J Clin Virol.2012;55:262–5. DOIPubMed
32. Imajoh M, Hashida Y, Taniguchi A, Kamioka M, Daibata M. Novel human polyomaviruses, Merkel cell polyomavirus and human polyomavirus 9, in Japanese chronic lymphocytic leukemia cases. J Hematol Oncol. 2012;5:25 . DOIPubMed
33. Rockett RJ, Sloots TP, Bowes S, O’Neill N, Ye S, Robson J, Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid. PLoS ONE. 2013;8:e62764. DOIPubMed
34. Hirsch HH, Steiger J, Polyomavirus BK. Lancet Infect Dis. 2003;3:611–23. DOIPubMed
35. Wieland U, Silling S, Hellmich M, Potthoff A, Pfister H, Kreuter A. Human polyomaviruses 6, 7, 9, 10 and trichodysplasia spinulosa–associated polyomavirus in HIV-infected men. J Gen Virol. 2014 [Epub ahead of print].

Figures

• Figure 1. Human polyomavirus 9 (HPyV9) DNA positivity and mean DNA viral load in transplant patients over time, the NetherlandsBars indicate percentage of HPyV9-positive patients; line indicates DNA loadTime points are...
• Figure 2. Human polyomavirus 9 (HPyV9) seropositivity and seroreactivity in samples from transplant patients and healthy blood donor controls collected 1 year apart, the NetherlandsBlack bars, baseline samples; white bars, follow-up...
• Figure 3. Kaplan-Meier curves showing proportional increase of human polyomavirus 9 (HPyV9) DNA–positive and seropositive transplant patients during 12-month follow-up, the NetherlandsA) Cumulative HPyV9 DNA positivity (viremia) for transplant patients who...
• Figure 4. Association between human polyomavirus 9 (HPyV9), BK polyomavirus (BKPyV), and cytomegalovirus (CMV) infection among transplant patients, the NetherlandsA) Percentage of HPyV9 DNA–positive samples among samples that tested negative (white...

Tables

• Table 1. Characteristics of patients and controls for study of human polyomavirus 9 prevalence among kidney transplant patients, the Netherlands
• Table 2. Detection of human polyomavirus 9 DNA and viral loads in kidney transplant patients and blood donors, the Netherlands

Technical Appendix

• Technical Appendix.  231 KB 

Suggested citation for this article: van der Meijden E, Wunderink HF, van der Blij-de Brouwer CS, Zaaijer HL, Rotmans JI, Bouwes Bavinck JN, et al. Human polyomavirus 9 infection in kidney transplant patients. Emerg Infect Dis [Internet]. 2014 Jun [date cited].http://dx.doi.org/10.3201/eid2006.140055

DOI: 10.3201/eid2006.140055