JC Virus Regulatory Region Tandem Repeats in Plasma and Central Nervous System Isolates Correlate with Poor Clinical Outcome in Patients with Progressive Multifocal Leukoencephalopathy

Sequencing results of the JCV RR. On the top is a representation of the MAD-1 and archetype JCV RR. The nucleotide numbers are based on the prototype MAD-1 sequence. The known transcription regulation factor binding sites are indicated and include the lytic control element (Lytic E), nuclear factor 1 (NF-1), and c-Jun. Each 98-bp unit is represented by an open box. The TATA box is represented by TATA. The archetype contains only one 98-bp unit with two inserts. Black box, 23-bp insert; checkered box, 66 bp-insert; dotted lines, deletions in the 98-bp units or in the 23- or 66-bp inserts; grey box, region downstream of the 98-bp units. Some clones contain fragments of this region inserted in the second 98-bp unit. MAD-1 contains an adenine at positions 85 and 183, compared with all other sequences that contain guanine at these positions. Asterisks, single mutations; scissors, single nucleotide deletions in the TATA box. (A) Sequencing results of HIV⁺ PML progressor patients 1 to 8. At the right of each sequence is the number of clones obtained per anatomic compartment. The first sequence of patient no. 1 has a large deletion in the second 98-bp unit that is replaced by a fragment identical to nucleotides 208 to 247 (striped box) containing an NF-1 predicted binding site and next to it a c-Jun binding site. Patient 3, 4, and 6 sequences have smaller fragments of the region nt 208 to 250 inserted in the second 98-bp unit; only the patient 3 sequence contains the full length of the NF-1 binding site. (B) HIV-negative PML progressors. (C) PML survivors. No. 11 is HIV⁺ and no. 12 is HIV⁻. (D) HIV⁺ patients with low CD4⁺ T-cell counts and other, non-PML neurologic disorders.