Advances in BK Virus Complications in Organ Transplantation and Beyond

Abstract

Reactivation of BK virus (BKV) remains a dreaded complication in immunosuppressed states. Conventionally, BKV is known as a cause for BKV-associated nephropathy and allograft dysfunction in kidney transplant recipients. However, emerging studies have shown its negative impact on native kidney function and patient survival in other transplants and its potential role in diseases such as cancer. Because BKV-associated nephropathy is driven by immunosuppression, reduction in the latter is a convenient standard of care. However, this strategy is risk prone due to the development of donor-specific antibodies affecting long-term allograft survival. Despite its pathogenic role, there is a distinct lack of effective anti-BKV therapeutics. This limitation combined with increased morbidity and health care cost of BKV-associated diseases add to the complexity of BKV management. While summarizing recent advances in the pathogenesis of BKV-associated nephropathy and its reactivation in other organ transplants, this review illustrates the limitations of current and emerging therapeutic options and provides a compelling argument for an effective targeted anti-BKV drug.

Keywords: BK virus, transplantation.

Figure 1

BK virus (BKV) biology. (A) BK virions are 45 nm in diameter, nonenveloped, and enclose the viral genome with host cell histones (packaged DNA is depicted in yellow and red on the right) surrounded by a capsid. The most abundant viral protein is VP1 (depicted in blue on the left and in gray on the right), which arranges in 72 pentamers to form the outer surface of the viral capsid, while the inner part of the capsid is composed of proteins VP2 and VP3 (depicted in blue and green on the right). Adapted from: Hurdiss et al. (B) BKV infection is initiated by the attachment of VP1 to polysialylated gangliosides (GD3, GD2, GD1b, and GT1b) and sialylated glycoproteins (1), followed by internalization (2). It then moves along microtubules to reach the endoplasmic reticulum (3), where chaperones, disulfide isomerases, and reductases partially uncoat the capsid (4) and release it into the cytosol (5). The viral genome is then transported (through interaction of VP2 and VP3 proteins with the importin α/β import pathway) into the nucleus for replication (6-7) followed by virion self-assembly in the nucleus (8). Virions are then released from the cell by cell lysis (9). (C) Genome map of BKV. BKV genome is ∼5 kb in length and replicates bidirectionally from a unique origin within the noncoding control region (NCCR; also called transcriptional control region [TCR]). The early coding region encodes 3 proteins by alternative splicing (large tumor antigen [TAg]; small tumor antigen [tAg]; and the truncated TAg; truncTAg), while the late genes encode structural protein, VP3 and Agno proteins), also by alternative splicing of a common pre-mRNA. The proteins encoded in the early coding region are mostly responsible for viral genome replication, with Tag being particularly important for making a quiescent cell reenter the cell cycle and replicate the viral genome. The structural proteins are important in viral attachment to susceptible cells, cell entry, viral propagation, and assembly of progeny virions.