ATC 2012 Report – Researchers shed light on the ways of the BK virus

by Thomas R. Collins – The BK virus, and damage to the kidney that is caused by it, poses a continuing challenge to kidney transplant specialists.

Researchers here at the 2012 American Transplant Congress presented findings that shed light on the way that the virus brings about the inflammation and fibrosis that can lead to graft loss, in the hope that more insight can lead to better treatment and outcomes.

The virus appears to cause changes in the genome of the host, which sets off the disease caused by the virus, said Lee Anne Tibbles, MD, Associate Professor at the University of Calgary and Director of the ALTRA Transplant Program in the southern Alberta region of Canada.

“What we’re proposing in these studies is that BK virus actually causes epigenetic changes into the host genome by adding methyl groups to certain CpG dinucleotides…. And that this epigenetic re-programming of the whole cell leads to the pathogenesis of this virus,” Dr Tibbles said. “These methylated cytosines actually prevent the attachment of transcription factor so they can silence genes.”

The BK virus problem has been brought about by the use of more powerful immunosuppressive drugs. Polyomavirus nephropathy has been found to occur in about 8% of kidney transplant recipients, and the BK virus is the one most often involved.

The most common treatment is reducing the use of immunosuppressives, which can boost the risk of rejection. So the virus requires a balancing act that is not always successful.

One gene that appears to be crucial to the process of BK virus is retinoblastoma, or RB1, a tumour suppressor gene, Dr Tibbles said.

Her lab found that in infected cells, inflammatory and fibrotic mediators — like Cox2, IL1B and Vimentin — are increased three- to five-fold — while expression of RB1 is suppressed.

“When expressed, it (RB1) reduces cell cycle so that silencing of this gene leads to increased proliferation of the cells,” Dr Tibbles said. “Infecting these cells with BK virus would reduce the proliferation activity of that promoter. And that’s a dose- dependent phenomenon, so the more BK that we put in (and) the higher the multiplicity of infection, the more that RB1 promoter activity is shut down. So this does seem to be related to BK infection.”

On the flip side, when RB1 is highly expressed, it inhibits BK replication.

“So BK actually requires shutting down this gene in order to replicate,” Dr Tibbles said. “The silencing of RB1 contributes to the proliferation of BK virus and BK-virus- induced epigenetic changes in the host epithelial cells, mainly to differentiation, increased cell cycle and increased migration — all of which are consistent with epithelial-to-mesenchymal transition of these renal epithelial cells as a pathogenic mechanism by which BK virus may cause fibrosis and graft loss.”

Dr Tibbles said it is unclear whether these changes are actually caused by one of the genes in BK directly or whether it’s some kind of secondary effect, but that her lab is exploring that question.

She said she and her colleagues are also looking for effects of the BK virus on other kinds of genes.

“We have a list of them and we’ll be going through and checking,” she said.

She said she hopes that the effects on genes might be a signal that can be useful in treating kidney recipients.

“Once we know that BK modifies RB1, for example, this could lead to biomarker detection,” she said. “If RB1 is silenced, then we would know that the virus is actually being pathogenic and changing the cells, whereas absence of that may lead to a better prognosis.”