Analysis of 15 novel full-length BK virus sequences from three individuals: Evidence of a high intra-strain genetic diversity

To determine the variability of BK virus (BKV) in vivo, the sequences of nine full-length molecular clones from the striated muscle and heart DNA of a patient with BKV-associated capillary leak syndrome (BKV_CAP), as well as three clones each from the urine of one human immunodeficiency virus type 2-positive (BKV_HI) and one healthy control subject (BKV_HC), were analysed. The regulatory region of all clones corresponded to the archetypal regulatory region usually found in urine isolates. Analysis of the predicted conformation of BKV_CAP proteins did not suggest any structural differences on the surface of the viral particles compared with BKV_HI and BKV_HC clones. No amino acid changes common to most BKV_CAP clones could be identified that have not already been reported in non-vasculotropic strains. However, the coding region of each clone had unique nucleotide substitutions, and intra-host variability was greater among BKV_CAP clones, with a mean difference of 0.29% per site compared with 0.16% for BKV_HI and 0.14% for BKV_HC. The clones from each strain formed monophyletic clades, suggesting a single source of infection for each subject. The most divergent BKV_CAP clones differed at 0.55% of sites, implying a rate of nucleotide substitution of approximately 5 × 10^-5 substitutions per site per year, which is two orders of magnitude faster than estimated for the other human polyomavirus, JC virus.