Studies on the polymorphism in the genome of polyomavirus BK: implications for cell tropism and the

Project leader(s)   Ugo Moens and Christine Hanssen Rinaldo

Co-workers / Project staff
Gunn-Hege Olsen, Berit Tømmerås

Main Objects:
This project wants to isolate and characterise naturally occurring BKV variants. Knowledge on the naturally circulating BKV strains in patients may help us to define the possible implications of genome diversity with respect to cell tropism and pathogenicity, and may enable us to design successful therapeutic strategies.

Project outline
The human polyomavirus BK (BKV) was originally isolated from the urine of a renal allograft recipient who developed ureteric stenosis and was named after the initials of this patient. Serological surveys have shown that BKV is distributed worldwide and has a high incidence among humans. Primary infection occurs predominantly during childhood and appears to be asymptomatic, although few cases of BKV-induced mild respiratory or urinary tract diseases, pyrexia, fatal disseminated infection, and hemorrhagic cystitis have been reported in immunosuppressed patients. After primary infection, BKV establishes a harmless latent infection in healthy individuals. BKV is a small non-enveloped DNA virus that belongs to the family of Polyomaviridae. Its genome can be divided in three functional domains: (1) the early region that encodes regulatory proteins, including the large T-antigen and small t-antigen; (2) the late region that encompasses the genetic information for the capsid proteins VP1, VP2, VP3, and the agnoprotein; and (3) the non-coding control region (NCCR) that spans the origin of replication (O-block, 142 base-pairs) and sequences involved in transcriptional regulation of both the early and the late genes. The transcriptional control region of the proposed archetypal BK strain WW has been arbitrarily divided into 4 transcription factor binding sequence blocks, called P (68 base-pairs), Q (39 base-pairs), R (63 base-pairs), and S (63 base-pairs) as depicted in Figure 1. The genomes of naturally occurring BKV strains display high sequence diversity, especially in the NCCR, but also in the other regions. Our group studies this genomic polymorphism in different patient groups. We also examine the functionality of putative transcription factor binding sites in the different NCCRs of naturally occurring BKV strains.

Genetic organization of BK virus. The dsDNA genome can be divided into three functional domains: the early region, encoding regulatory proteins, the late region encoding the capsid proteins VP1 to VP3, and the regulatory agnoprotein, and the non-coding control region that spans the origin of replication and the transcriptional control region.

Collaborators / Partners
Collaborators
-Dr. Marijke Van Ghelue, Department of medical Genetics, University Hospital, Tromsø

Publications
Immunity and autoimmunity induced by polyomaviruses: clinical, experimental and theoretical aspects.
Adv Exp Med Biol. 2006;577:117-47.

Moens, U., and Van Ghelue, M. (2005). Polymorphism in the genome of non-passaged human polyomavirus BK: implications for cell tropism and the pathological role of the virus. Virology 3312:209-31.

Rinaldo CH, Myhre MR, Alstad H, Nilssen O, Traavik T. 2003. Human polyomavirus BK (BKV) transiently transforms and persistently infects cultured osteosarcoma cells. Virus Res. 93:181-7.

Moens U, Rekvig OP. (2001). In: The Human Polyomaviruses JC, BK, and SV40: Molecular and Clinical Perspectives. (K. Khalili and G.L. Stoner, eds). Wiley and Sons, New York. Pp.359-408.

Bendiksen S, Rekvig OP, Van Ghelue M, Moens U. 2000. VP1 DNA sequences of JC and BK viruses detected in urine of systemic lupus erythematosus patients reveal no differences from strains expressed in normal individuals. J Gen Virol. 81:2625-33.

Sundsfjord A, Osei A, Rosenqvist H, Van Ghelue M, Silsand Y, Haga HJ, Rekvig OP, Moens U. 1999. BK and JC viruses in patients with systemic lupus erythematosus: prevalent and persistent BK viruria, sequence stability of the viral regulatory regions, and nondetectable viremia. J Infect Dis. 180:1-9.

Moens U, Van Ghelue M, Johansen B, Seternes OM. 1999. Concerted expression of BK virus large T- and small t-antigens strongly enhances oestrogen receptor-mediated transcription. J Gen Virol. 80:585-94.

Moens U, Seternes OM, Johansen B, Rekvig OP. (1997). Mechanisms of transcriptional regulation of cellular genes by SV40 large T- and small T-antigens. Virus Genes. 15:135-54.

Moens U, Johansen T, Johnsen JI, Seternes OM, Traavik T. (1995). Noncoding control region of naturally occurring BK virus variants: sequence comparison and functional analysis. Virus Genes. 10:261-75.

Moens U, Subramaniam N, Johansen B, Johansen T, Traavik T. 1994. A steroid hormone response unit in the late leader of the noncoding control region of the human polyomavirus BK confers enhanced host cell permissivity. J Virol. 68:2398-408.