BK polyomavirus, commonly known as BKPyV, is a significant factor leading to kidney transplant failures, and there are currently no effective medications available to treat it. Recent studies from the University of Alabama at Birmingham have uncovered new insights into how BKPyV replicates, which may lead to potential drug targets for safeguarding transplanted kidneys.
BK polyomavirus, or BKPyV, is a major cause of kidney transplant failure. There are no effective drugs to treat BKPyV. Research at the University of Alabama at Birmingham reveals new aspects of BKPyV replication, offering possible drug targets to protect transplanted kidneys.
In order to delve deeper into BKPyV replication and explore prevention strategies, researchers from the UAB Department of Microbiology have conducted a single-cell analysis of BKPyV infection in primary kidney cells. Their research challenges the previously accepted views on the molecular processes needed for BKPyV production, suggesting potential new drug targets to protect kidney transplants, according to Sunnie Thompson, Ph.D., an associate professor. This study has been published in the journal PLOS Pathogens.
BK polyomavirus, having only seven genes, relies on the host cell’s DNA replication machinery to generate new viruses. Although the virus has been known for over half a century, there is still a limited understanding of how BKPyV gains access to the cell’s replication processes.
Lead author Jason M. Needham, Ph.D., explains that “this research emerged from an apparent contradiction.” BKPyV appears to activate a markedly different cell cycle, even while simultaneously triggering cellular pathways intended to inhibit the cell cycle.
The traditional model posits that BKPyV expresses a protein known as large tumor antigen, or TAg, early in the infection process. It was believed that early TAg expression prompted kidney cells to initiate DNA replication, which would grant the virus the access it requires to the replication machinery. Hence, TAg was expected to be expressed before the cells began their DNA duplication.
However, Needham, who is a graduate student of Thompson, conducted a single-cell cycle analysis on BKPyV-infected kidney cells and was surprised to find that TAg expression was non-existent prior to the first round of cellular DNA replication. Instead, TAg levels surged 100-fold as the cells completed their initial round of DNA replication. This timing implied that TAg was expressed too late to be the force driving cells to replicate their DNA.
Both TAg expression and viral replication took place after the initial round of host DNA replication, and TAg expression relied on the completion of this first replication cycle. When Needham inhibited this initial round of cellular DNA replication, using inhibitors specifically targeting the cell’s DNA replication without affecting the virus, TAg was never expressed, and viral production did not occur. However, if DNA replication was inhibited after this first round, when TAg was already present, the ongoing host replication was no longer necessary for sustaining TAg expression or viral production.
Thompson noted that “since TAg expression is crucial for virus replication, this implies that inhibiting DNA synthesis in kidney cells shortly after infection could thwart BKPyV replication.”
Additionally, the UAB researchers discovered that once TAg was produced, the virus maintained a replicative environment dependent on the regular machinery and regulators of the host cell cycle. It was already established that BKPyV infection halts cell division, leading to enlarged cellular nuclei filled with DNA from multiple rounds of cellular DNA replication without division. More research is needed to determine whether the significant TAg expression following a single round of host DNA replication causes the cells to re-enter DNA replication while avoiding cell division instead of undergoing usual division.
The findings indicate that inhibitors targeting the cellular proteins essential for sustained re-replication would be beneficial in treating kidney cells actively replicating BKPyV, while sparing the normal cell cycle. Targeting host proteins decreases the chance of viruses evolving resistance to drugs, as they do not possess genetic control over the drug targets.
Thompson emphasizes that there is still much to learn about BKPyV’s dependence on and promotion of DNA replication in kidney cells. This includes understanding the process of how DNA replication is triggered post-BKPyV infection; if it isn’t due to early TAg expression, then what is the mechanism? Moreover, the specific mechanisms that regulate BKPyV reactivation in human kidneys, alongside the intricate details of its in-vivo life cycle, remain unresolved.
Co-authoring with Thompson and Needham in the study titled “Single-cell analysis reveals host S phase drives large T antigen expression during BK polyomavirus infection,” is Sarah E. Perritt from the UAB Department of Microbiology.
Funding for this research was provided by National Institutes of Health grants AI123162, AI178734, and GM008111.
The Microbiology department at UAB is part of the Marnix E. Heersink School of Medicine.
