Persistence of polyomavirus : versus immunity to polyoma tumors

Abstract: The aim of this thesis was to understand the role of different specific immune effectors with regard to polyomavirus persistence and polyomavirus induced tumor development. Furthermore, an MHC class I restricted short viral peptide was identified as a target for polyomavirus specific recognition of polyoma tumor cells. Persistence of polyomavirus was followed with a polyoma specific polymerase chain reaction (PCR) in immunocompetent and immunodeficient mice. Persistent polyomavirus DNA could not be detected in normal adult infected mice, in contrast to that observed in normal newborn mice. Persistence of polyomavirus in newborn mice and later tumor development were suggested to be due to that newborn mice do not have a fully matured immune system. In order to specifically analyze the importance of different immune effectors with regard to polyoma persistence, polyomavirus infection was followed in mice with various immune deficiencies. In adult severe combined immune deficiency (SCID) mice, lacking both functional T-, and B-cells, an extensive spread of polyomavirus was observed and the mice succumbed to the infection. In adult CD4-/- or CD8-/- single knockout mice with only one T-cell population, infection with polyomavirus was limited and cleared around 1 month p.i. in most of the animals. However, in CD4-/-8-/- double knockout mice lacking both T-cell populations a more extensive viral spread was observed, and a persistent polyoma infection was established. Among neonatally infected mice, a proportion of normal, CD4-/- or CD8-/- single knockout and CD4-/-8-/- double knockout mice harbored persistent polyoma DNA several weeks p.i. The frequency of polyoma tumor development was, however, significantly higher in CD4-/-8-/- double knockout mice (29%) compared to CD4-/- or CD8-/- single knockout mice (2% and 11% respectively) and normal mice (6%). Polyomavirus persistence was also followed in adult mice deficient in antibody production. In adult X-linked immune deficiency (XID) mice, with a decreased B-cell count, polyomavirus persistence was established in approximately one third of the mice. IgM-/- single knockout and IgM-/-CD8-/- double knockout mice harbored persistent polyomavirus in most organs 6-12 weeks p.i. MHC class I restricted peptides were eluted from the surface of a polyoma positive tumor and a short peptide was identified as possible tumor specific transplantation antigen (TSTA). The peptide was a nonamer corresponding to amino acid (aa) sequence 578-586 of polyoma Large T-antigen (LT). In vivo tumor rejection tests showed that a shorter version of this peptide corresponding to LT 578-585 was the most effective as an immunogen. Key words: polyomavirus persistence, CD4-/-, CD8-/-, IgM-/-, XID, SCID, TSTA, T-antigen, tumor rejection. ISBN-91-628-2372-8

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