Journal of General Virology (1999), 80, 1017–1023. Printed in Great Britain ................................................................................................................................................................................................................................................................................... Archetypal and rearranged sequences of human polyomavirus JC transcription control region in peripheral blood leukocytes and in cerebrospinal fluid S. Ciappi, 1 A. Azzi, 1 R. De Santis, 1 F. Leoncini, 2 G. Sterrantino, 2 F. Mazzotta 3 and L. Mecocci 3 1 Istituto di Microbiologia, Universita  di Firenze, Viale Morgagni 48, 50134 Firenze, Italy 2 Unita  di Malattie Infettive, Azienda Ospedaliera di Careggi, Firenze, Italy 3 Unita  di Malattie Infettive, Ospedale Santa Maria Annunziata, Firenze, Italy Two forms of human polyomavirus JC (JCV) genome are known based upon the structure of the transcriptional control region (TCR) of the virus : the archetypal form, which is commonly detected in urine, and the rearranged form, which was first detected in brain tissue from progressive multifocal leukoencephalopathy (PML) patients. The latter actually includes a group of TCR variants that, relative to the former, are characterized by various deletions and/or duplications. The aim of this study was to establish whether or not a correlation exists among the TCR type, the spreading of the virus within the host and its ability to cause PML. JCV TCR sequences from peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) obtained from various groups of patients were compared. JCV with archetypal TCR was detected in CSF and PBL specimens from patients without neurological disorders or who eventually received a diagnosis of a non-PML neurological disorder. Rearranged TCR sequences were detected in all the CSF and PBL specimens from PML patients. The high similarity observed between the TCR structure detected in PBL and CSF specimens from individual patients could strengthen the hypothesis that PBL has a role in spreading JCV to the brain. Moreover, heterogeneous TCR patterns have been shown in individual PBL specimens from PML patients. This supports the hypothesis that, in PBL, JCV may replicate and undergo rearrangements of the TCR. The detection of JCV DNA by PCR in CSF independently from PML, although rare, could suggest that this assay is not sufficient for a virological diagnosis of PML. Further studies are required to assess the usefulness of quantitative assays or TCR typing in combination with PCR for diagnostic purposes. Introduction Human polyomavirus JC (JCV) infection is widespread in the human population as inferred by serological surveys (Walker & Padgett, 1983). However, the route of transmission and the site of initial infection in the body have not yet been detected, mainly because of the asymptomatic nature of the primary infection. More information, although this is still incomplete, is known about the events that follow initial exposure. In fact, it Author for correspondence : Alberta Azzi. Fax 39 055 4223895. e-mail microunifi.it The GenBank accession numbers of the sequences reported in this paper are AF030114–AF030128. has been documented that JCV persists in the kidney, in the bone marrow and haematopoietic system, in peripheral blood leukocytes (PBL) and also in the brain (Chester et al., 1983; Houff et al., 1988; Elsner & Do  rries, 1992 ; White et al., 1992 ; Do  rries et al., 1994). Virus reactivation may ensue under different conditions such as an impairment of T cell-mediated immunity or the influence of cytokines on viral gene expression (Atwood et al., 1995; Chang et al., 1996). In the kidney, reactivation of the latent JCV may result in its asymptomatic shedding in the urine of both immunocompromised and immunocompetent individuals (Markowitz et al., 1993 ; Azzi et al., 1996). In the brain, JCV lytic infection of myelin-producing oligodendrocytes causes progressive multifocal leukoence- phalopathy (PML), a fatal progressive demyelinating disease. This disease occurs in patients with severe and long-lasting 0001-5877  1999 SGM BABH