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

Abstract

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 5610 "5 substitutions per site per year, which is two orders of magnitude faster than estimated for the other human polyomavirus, JC virus.

Interplay of Cellular and Humoral Immune Responses against BK Virus in Kidney Transplant Recipients with Polyomavirus Nephropathy

“…Although we have recently detected a higher intrastrain genetic diversity in BKV sequences (6) than previously reported for JCV (16), the two BKV CTL epitopes identified in this study are conserved among all 23 different BKV strains, including the 15 complete genomes sequenced by our group, except for a single amino acid change in one epitope of one strain (6), and among 445 JCV sequences available in GenBank. These results suggest that generation of JCV or BKV CTL epitope escape mutants may be unlikely to occur.…”

Sp1 Sites in the Noncoding Control Region of BK Polyomavirus Are Key Regulators of Bidirectional Viral Early and Late Gene Expression

“…The other case was a kidney transplant patient with nephropathy, who developed a generalized capillary leak pathology with fatal outcome (28). The BKPyV genome showed no evidence of NCCR rearrangements, but a point mutation in ETS1-2 (29). Our results now indicate that this mutation abrogates Ets1 binding similarly to the group 1 mutation generated experimentally, causing an activated EVGR expression.…”

“…A database search revealed that the ETS1-2 site was altered in two clinical cases with significant BKPyV disease. The first case was an HIV-1 infected patient with BKPyV-associated hemorrhagic cystitis (29). Here, the mutant ets1-2 sequence was predicted to abrogate Ets1 binding, while a novel Sp1 site was potentially created.…”

“…Group 2 and group 3 mutants showed intermediate and low gene expression, respectively. In a database search, we identified corresponding mutations in the BKPyV NCCRs from patients with significant BKPyV pathology, such as nephropathy, hemorrhagic cystitis, and disseminated infection, that had not been identified as viral pathology determinants (27)(28)(29). Our results provide new insights into how polyomavirus NCCRs function through specific TFBS and shed new light on how Sp1 controls bidirectional BKPyV gene expression and its role in BKPyV pathology.…”

Identification of the novel KI Polyomavirus in paranasal and lung tissues

“…JCV can cause a demyelinating disease known as progressive multiphocal leukoencephalopathy (PML) which occurs mainly in AIDS patients [Gordon and Khalili, 1998]. BKV can be responsible of a tubular nephritis, which can lead to allograft failure in renal transplant recipients and hemorrhagic cystitis in hematopoietic stem cell transplant recipients [Nickeleit et al, 2002;Hirsch and Steiger, 2003;Chen et al, 2004].…”