Studies on polyomaviruses in humans : in relation to haematopoietic stem cell transplantation and cancer

The simultaneous discovery of two polyomaviruses in humans in 1971, BK and JC viruses (BKV and JCV), initiated the research on polyomaviruses in relation to human diseases. This has now been intensified with the consecutive discoveries, the last three years, of three new family members, KI, WU and Merkel cell polyomaviruses (KIPyV, WUPyV and MCPyV). Notably, the frequent and reproductive presence of MCPyV in Merkel cell carcinoma, a rare skin cancer of the elderly, has opened new perspectives for polyomavirus research in humans. The ultimate aim of this thesis was to understand, prevent and cure tumour development and disease associated to polyomavirus infection in humans.

BKV is ubiquitous and infects humans in early childhood without any symptoms. In the context of allogeneic haematopoietic stem cell transplantation (HSCT), BKV can reactivate and has been associated to haemorrhagic cystitis complication (HC), usually occurring within three months after HSCT. Between 2002 and 2006, by following prospectively 175 allogeneic HSCT patients at the Karolinska University hospital Huddinge and collecting their urine samples weekly, we have been able to confirm the significant role of BKV in the risk of developing HC. In papers I, II and III we have also identified additional factors that contribute to the prediction of this complication. More specifically, full myeloablative conditioning and an unrelated donor graft significantly put the patients at risk for HC. A tendency to develop HC was also observed in patients receiving an HLA mismatched transplant. Acute graft-versus-host disease, could however not be confirmed as risk factors for HC. There was also no significant difference in the frequency of HC if the patients received stem cells from peripheral blood or bone marrow, while the risk for HC after using umbilical cord blood needs to be investigated further.

In this thesis, we also especially investigated the role of the new polyomaviruses in relation to some specific human cancers. In paper IV, we tested 38 mucosal melanomas for the presence of BKV, JCV, KIPyV, WUPyV and MCPyV DNA. Mucosal melanomas are malignant tumours of the skin areas that are not exposed to UV-light. Therefore, some aetiological factors, like viruses, remained to be uncovered. The absence of any polyomavirus tested suggests that these viruses do not play an aetiological role in these tumours.

In paper V we tested 31 neuroblastomas and 25 childhood CNS tumours for the presence of the recently discovered KIPyV, WUPyV and MCPyV. The absence of these viruses, despite highly sensitive methods and good DNA quality, suggests again that these viruses are not involved in these paediatric nervous system tumours. However, the results from the 25 CNS tumours remain preliminary since this material included a variety of diagnostic subsets. Furthermore, our results do not exclude the possibility that other so far not detected infectious agents could be involved in this disease.

List of scientific papers

I. Bogdanovic G, Priftakis P, Giraud G, Kuzniar M, Ferraldeschi R, Kokhaei P, Mellstedt H, Remberger M, Ljungman P, Winiarski J, Dalianis T (2004). "Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation." J Clin Microbiol 42(11): 5394-6
https://pubmed.ncbi.nlm.nih.gov/15528753

II. Giraud G, Bogdanovic G, Priftakis P, Remberger M, Svahn BM, Barkholt L, Ringden O, Winiarski J, Ljungman P, Dalianis T (2006). "The incidence of hemorrhagic cystitis and BK-viruria in allogeneic hematopoietic stem cell recipients according to intensity of the conditioning regimen." Haematologica 91(3): 401-4
https://pubmed.ncbi.nlm.nih.gov/16531266

III. Giraud G, Priftakis P, Bogdanovic G, Remberger M, Dubrulle M, Hau A, Gutmark R, Mattson J, Svahn BM, Ringden O, Winiarski J, Ljungman P, Dalianis T (2008). "BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts." Bone Marrow Transplant 41(8): 737-42. Epub 2008 Jan 7
https://pubmed.ncbi.nlm.nih.gov/18176615

IV. Giraud G, Ramqvist T, Ragnarsson-Olding B, Dalianis T (2008). "DNA from BK virus and JC virus and from KI, WU, and MC polyomaviruses as well as from simian virus 40 is not detected in non-UV-light-associated primary malignant melanomas of mucous membranes." J Clin Microbiol 46(11): 3595-8. Epub 2008 Sep 3
https://pubmed.ncbi.nlm.nih.gov/18768658

V. Giraud G, Ramqvist T, Pastrana DV, Pavot V, Lindau C, Kogner P, Orrego A, Buck CB, Allander T, Holm S, Gustavsson B, Dalianis T (2009). "DNA from KI, WU and Merkel cell polyomaviruses is not detected in childhood central nervous system tumours or neuroblastomas." PLoS One 4(12): e8239
https://pubmed.ncbi.nlm.nih.gov/20011509