Rearrangement of the JC-virus genome - The transformation from a benign type to a PML virus

Abstract

JC-virus (JCV) is present in approximately 90% of the human population and is the causative agent of progressive multifocal leukoencephalopathy (PML). JCV is usually present in the kidneys or urogenital tract and does not lead to disease or noticeable symptoms in healthy individuals. In certain cases however JCV may mutate from a benign viral type known as archetype to a malignant, PML causing type. This consequence is especially seen in HIV-infected patients and individuals undergoing immunosuppressive theory. We present two theories that may explain how this transformation may occur. Piling evidence exists that JCV influences DNA repair mechanisms in infected cells. Both agnoprotein and large-T protein have been shown to play an important role in this process. The extent of the influence on DNA repair suggests a more crucial role for this process than merely support of cell lysis. A close family member of JCV, SV40, also influences DNA repair mechanisms and hijacks cellular systems to recombine its genome. This supports the possibility that JCV may use a similar mechanism. Another theory regarding JCV genome recombination involves B-cells, which undergo VDJ-recombination when maturating. B-cells have been observed to be infected by JCV. Important support for this theory is that the genome of the PML variant of JCV contains duplicated Spi-B binding sites. Spi-B is a very important factor in maturating B-cells and is present in uniquely high levels in B-cells. It has been shown that DNA damage is also induced in lymphocytes, which links the DNA damage theory to the B-cell theory. Possibly JCV induces damage in B-cells, activating DNA damage repair mechanisms and simultaneously hijacks the VDJ-recombination to rearrange its genome and become a PML virus. We conclude that these two theories may both comprise part of the true mechanism.