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Regardless of the site of viral latency or which of the above models is correct, the fundamental premise is that at least four events must occur before latent JCV can cause lytic infection of oligodendrocytes in the brain: (i) the host immune system must be compromised; (ii) the viral NCCR (discussed in more detail below) must acquire changes that increase viral transcription and replication in both B cells and glial cells; (iii) transcription factors that bind to the recombined NCCR sequence motifs must be present and/or upregulated in infected haematopoietic progenitor, B cells, and/or glial cells; (iv) free virus or virus in B cells must cross the BBB and be carried to the brain, where the virus is passed to oligodendrocytes and lytic infection takes place .
The PyV NCCR is the most variable portion of the viral genome, both within a single virus, as well as across genera of viruses [80-86].
Finally, viral-associated factors have been implicated in BKVN, and BKV NCCR and VP1 mutations have been described; however, it is unclear whether this may simply arise from a preexisting lack of immune control of viral replication which would naturally lead to higher viral sequence diversity [201,202].
Two mutational events following a loss of immune surveillance appear critical to cancer development in MCC patients; firstly, MCV is clonally integrated in an apparently unbiased location in the tumour genomes, and, secondly, the TAg helicase domain associated with NCCR binding and thus viral (lytic) replication is abolished; however, all mutations downstream of the LXCXE Rb tumour suppressor-binding motif are retained [4, 229].
Crowley, "Unique BK virus non-coding control region (NCCR) variants in hematopoietic stem cell transplant recepients with and without hemorrhagic cystitis," Journal of Medical Virology, vol.
Conversely, the non coding control region (NCCR) sequence is hypervariable and contains determinants for neurotropism and neurovirulence.
The early and late genes are physically separated by the NCCR that is the most variable portion of the viral genome.
NCCR recombination may lead to acquisition of transcription factor binding sites that are important for pathogenesis.
Interestingly, the interaction between HIV Tat and cellular Pur-[alpha] has been shown to play a role in DNA repair , which could potentially cause increased JCV rearrangements in coinfected cells, leading to an increased chance of JCV NCCR sequences associated with PML.
Recombination of DNA in B cells also offers an attractive model for the changes in the viral NCCR that are necessary to increase pathogenicity and replicative efficiency of the virus in glial cells (see below) [4, 53].
TAg binds preferentially to a site located in the viral DNA ori, closest to first TATA box in the NCCR. When TAg binds JCV DNA, it promotes the YB-1/Pur-[alpha] switch to viral late gene transcription.
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