Biology of the BKPyV: An Update

Abstract

The BK virus (BKPyV) is a member of the Polyomaviridae family first isolated in 1971. BKPyV causes frequent infections during childhood and establishes persistent infections with minimal clinical implications within renal tubular cells and the urothelium. However, reactivation of BKPyV in immunocompromised individuals may cause serious complications. In particular, with the implementation of more potent immunosuppressive drugs in the last decade, BKPyV has become an emerging pathogen in kidney and bone marrow transplant recipients where it often causes associated nephropathy and haemorrhagic cystitis, respectively. Unfortunately, no specific antiviral against BKPyV has been approved yet and the only therapeutic option is a modulation of the immunosuppressive drug regimen to improve immune control though it may increase the risk of rejection. A better understanding of the BKPyV life cycle is thus needed to develop efficient treatment against this virus. In this review, we provide an update on recent advances in understanding the biology of BKPyV.

Keywords: Agno; ERAD; TAg; VP1; archetype; ganglioside; noncoding control region; polyomavirus; rearranged form.

Figure 1

Cryo-electron microscopy structure of BK virus (BKPyV) viral particles (Adapted from [11]). (A) External view of the BKPyV virion shown at a contour level of 0.022. A viral protein VP1 pentamer is highlighted; (B) View of a 40-Å-thick slab through the unsharpened/unmasked virion map shown at a contour level of 0.0034. Pyramidal density below each VP1 penton and two shells of electron density adjacent to the inner capsid layer can be seen. The density within 6 Å of the fitted coordinates for SV40 VP1 is coloured grey. Density for VP2 and VP3 is coloured blue/green and for packaged double stranded DNA (dsDNA) yellow/pink.

Figure 2

Genome map of BKPyV. (Bottom) The BKPyV genome is a closed circular, double-stranded DNA molecule of approximately 5 kb. The transcription of early and late coding regions proceeds in a bidirectional way from the origin of replication (ORI) that is located within the noncoding control region (NCCR). The early coding region encodes large tumour antigen (Tag), small tumour antigen (tAg) and truncated TAg (truncTAg) that are produced from different alternatively spliced mRNAs. Introns in the early coding region are represented by double lines. The late coding region encodes the structural proteins VP1, VP2 and VP3 as well as the Agno protein. These proteins are translated from two classes of late RNAs, 16S and 19S, that are generated by alternative splicing from a common pre-mRNA. The 19S RNA is translated to yield both VP2 and VP3 while the 16S RNA species is translated to yield Agno and VP1. The BKPyV genome also encodes two miRNAs, 5p-miRNA and 3p-miRNA, produced after processing of a common pre-miRNA hairpin and perfectly complementary to the TAg encoding mRNAs. (Top) The schematic organization of the BKPyV archetype non-coding control region (NCCR) is represented. It is divided into five sequence blocks (O, P, Q, R and S). It includes the origin of replication (ORI), TATA box and TATA-like elements. The positions of different sites important for the binding of TAg and the transcription factors Sp1, NF1, Ets-1 and nuclear factor κB (NF-κB), as well as cAMP-, phorbol ester-, glucocorticoid/progesterone- and oestrogen responsive-elements (CRE, TRE, GRE/PRE and ERE, respectively) are also mentioned. CRE: cAMP responsive-element; TRE: phorbol ester responsive-element; GRE/PRE: glucocorticoid/progesterone responsive-element; ERE: oestrogen responsive-element.

Figure 3

Model of the BKPyV life cycle. BKPyV infection begins with binding of virions to the ganglioside receptors (particularly GT1b and GD1b) and/or an N-linked glycoprotein containing α(2,3)-linked sialic acid, at the cell surface (1). This is followed by internalization potentially through a caveola-mediated endocytosis step within the first 4 h after adsorption (2). The virus subsequently traffics from the late endosomes to the endoplasmic reticulum (ER), where it arrives approximately 10 h post-infection (3). In the ER, virions benefit from chaperones, disulphide isomerases and reductases to facilitate the partial capsid uncoating. This creates a hydrophobic surface exposing VP2/VP3 that binds to and integrates into the ER membrane, leading to the release of partially uncoated viruses into the cytosol, a process that also involves the ER-associated protein degradation (ERAD) machinery (4). The viral genome is then transported into the nucleus via the nuclear pore complex thanks to VP2/VP3 NLS and the importin α/β1 import pathway (5). Expression of early genes occurs approximately 24 h post-infection (6). Early proteins are translocated into the nucleus where they serve to initiate viral DNA replication (7). Late genes are then expressed (8). VP1, VP2 and VP3 are translocated into the nucleus where they self-assemble to form capsids into which newly synthetized double stranded viral DNA is packaged (9). Progeny virions are mainly released from infected cells after cell lysis (10). However, a small fraction of progeny virions may also be released into the extracellular environment through a non-lytic egress that depends on the cellular secretion pathway (11).