Archetype Regulatory Sequence

Sero-epidemiologic studies have shown that JCV circulates in humans without any obvious symptoms (Padgett and Walker, 1973, 1976). Indeed, JCV is frequently excreted in the urine of healthy individuals as well as patients without PML (Kitamura et al., 1990, 1994a; Agostini et al., 1996). Yogo et al. (1990) cloned JCV DNA directly from two healthy volunteers and eight nonimmu-nocompromised patients. Restriction enzyme analysis confirmed that the overall genome structure of the urine-derived isolates was identical with that of PML-type isolates. The regulatory region sequences of the 10 urine-derived isolates were then analyzed. The basic structure of the regulatory region was identical among clones derived from all individuals, with a few nucleotide mismatches (the regulatory sequence of a clone from a healthy individual, CY, is shown in Fig. 7.1). Where multiple clones from the same individual were examined, the structure of the regulatory region was identical among clones examined, with a single exception. Thus, it was concluded that the regulatory regions of JCVs derived from the urine of nonimmunocompromised individuals are highly homogeneous, in marked contrast with the hypervariable regulatory regions of PML-type JCVs.

The regulatory region of the JCV DNA cloned by Yogo et al. (1990) lacked any repetition of a sequence of significant length (Fig. 7.1). It contained 23 and 66 bp sequences, which were inserted into the 98 bp sequence present in a tandem repeat in Mad-1. As a result, the 98 bp sequence was split into three portions of 25, 55, and 18 bp (Fig. 7.1). The 23 bp sequence had been identified in a majority of PML-derived variants, although it was absent in a few, including Mad-1 (Frisque et al., 1984; Martin et al., 1985). As described below, it was later found that a significant number of isolates from the brain and cerebrospinal fluid (CSF) of PML patients retained a region encompassing the 66 bp sequence (Ault and Stoner, 1993; Agostini et al., 1997a; Sugimoto et al., 1998). The regulatory sequence depicted in Figure 7.1 was designated as

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