Viral study suggests approach to reduce kidney damage in transplant patients

By studying one of the smallest known DNA viruses, Sunnie Thompson, Ph.D., may have found a new way to prevent kidney damage after an organ transplant.

A researcher from the University of Alabama in Birmingham is studying BK polyomavirus, a major source of kidney damage and rejection in transplant recipients. Almost all humans silently harbor polyomaviruses in their bodies; but when transplant recipients receive drugs to suppress their immune system and prevent rejection of the transplant, the virus can reactivate, leading to kidney damage.

No FDA approved treatment exists to control BK polyomavirus. Thompson, an badociate professor in the department of microbiology at UAB, says that while their findings may be verified in human patients, they may have discovered a new way to reduce BK polyomavirus levels in transplant patients without reducing immunosuppressive drugs necessary for the prevention of transplant rejection.

Thompson's findings come from basic research on the virus, now published in an article in the Virology Journal.

With only seven genes, the polyomavirus must control the replication mechanisms of the host cell's DNA in order to produce new viruses. To do this, the virus forces host cells to begin replicating to subvert the cell's proteins to make copies of the virus. Viral replication activates a response to DNA damage; but it was unclear why this was important for viral replication, so Thompson's lab sought to understand how the activation of the DNA damage response helped the virus.

The reaction to DNA damage involves two major proteins called ATM and ATR, which are recruited from sites of DNA damage. The activation of this response leads to the repair of DNA, stopping cell replication during DNA repair or cell death if the damage to the DNA occurs. DNA are too serious. Thompson and his colleagues inhibited the ATM or ATR in infected cells, which revealed that the virus was activating the DNA damage response in order to stop the cell cycle. This kept the cell's proteins available to continue to reproduce the virus.

When ATR was inhibited in cells infected with BK polyomavirus, the infected cells began to divide while they still made DNA. This resulted in serious damage to the DNA and a decrease in viral production.

The role of ATM was different. ATM was needed for the virus to begin replication of the host's DNA. ATM also prevented the cell from entering mitosis, but only after the end of DNA replication, which resulted in a reduction in viral production, but no damage to the DNA.

Importantly, these inhibitors did not alter the cell cycle nor increase the damage to DNA in uninfected cells. Only BK polyomavirus-infected cells treated with these inhibitors showed increased cell division, which reduced viral titers. Since these inhibitors are already undergoing clinical trials as anticancer drugs, this could be an opportunity to use them to reduce BK polyomavirus levels in kidney transplant patients with polyomavirus infections. BK active. The current standard of care is to reduce the number of drugs that inhibit the immune system, which increases the risk of transplant rejection.